cetpinhibition.org · CETP Inhibition: Science, Trials & Evidence

CETP variants rs2033254 and rs12708980 associate with lower intestinal cholesterol absorption markers in a European GWAS (Nutrients 2026)

Fri, 28 Aug 2026 06:36:25 +0200

This genome-wide association study in 398 healthy Europeans identified two single-nucleotide polymorphisms in CETP (rs2033254 and rs12708980) associated with lower total cholesterol-standardized campesterol and sitosterol levels. The analysis evaluated 166,037 common genetic variants and found 16 associated SNPs, with two reaching genome-wide significance across both absorption markers. These findings position CETP as a genetic determinant of intestinal cholesterol absorption, though the modest sample size and lack of functional validation require independent replication before clinical translation.

CETP rs3764261 genotype modifies the HDL-C lowering effect of a vegetarian diet in 9,263 adults (Taiwan Biobank) (Front Nutr 2026)

Fri, 21 Aug 2026 05:57:32 +0200

This Taiwan Biobank cohort analysis of 9,263 adults examined whether CETP rs3764261 genotype modifies the association between vegetarian diet and HDL-C levels. Vegetarians had significantly lower mean HDL-C than non-vegetarians (53.190 vs. 56.031 mg/dL). The HDL-C-raising effect of CA and AA genotypes was evident only among non-vegetarians, while the HDL-lowering effect of a vegetarian diet increased progressively across CC, CA, and AA genotypes (β = -2.6779, -4.8479, and -8.1884 mg/dL, respectively; p for interaction = 0.0045). These findings support gene-diet interactions in precision lipid management, though the small number of AA homozygotes among vegetarians (n = 21) limits statistical power and warrants replication.

CETi-1, AVANT Immunotherapeutics CETP-targeting vaccine, entered Phase II trials for hypercholesterolemia and atherosclerosis by 2001 (Curr Opin Investig Drugs 2004)

Wed, 19 Aug 2026 20:56:33 +0200

CETi-1 is a vaccine that stimulates antibodies specific for cholesteryl ester transfer protein (CETP), developed by AVANT Immunotherapeutics for potential use in reducing atherosclerosis risk factors. Phase II trials of CETi-1 in hypercholesterolemia and atherosclerosis had been initiated by August 2001.

Bariatric-surgery weight loss of 28.7 kg lowers CETP mass 27% and activity 25% in morbidly obese women, alongside an increase in LDL particle size (Arterioscler Thromb Vasc Biol 2002)

Wed, 19 Aug 2026 20:56:28 +0200

Obesity increases morbidity and mortality from atherosclerotic disease, partly through an atherogenic lipoprotein pattern that may be mediated by increased cholesteryl ester transfer protein (CETP) mass. The authors studied twenty-one morbidly obese, middle-aged women before and one year after surgical weight-loss treatment, measuring fat mass by bioimpedance, CETP mass by ELISA, CETP activity by exogenous substrate assay, and LDL particle diameter by gradient gel electrophoresis. Mean weight loss after one year was 28.7 kg, with mean fat mass loss of 22.6 kg. Mean CETP mass decreased from 1.81 to 1.32 microgram/mL (P=0.008), mean CETP activity decreased from 244 to 184 nmol per mL per hour (P=0.004), and mean LDL particle diameter increased from 256.8 to 258.4 Angstrom (P=0.04). Weight loss thus decreases CETP mass and activity while increasing LDL particle diameter.

In type 1 diabetic children, arachidonic acid content of LDL cholesteryl ester correlates with CETP activity independent of CETP concentration, suggesting a route to excess LTB4 (Med Hypotheses 2002)

Wed, 19 Aug 2026 20:56:27 +0200

Elevated cholesteryl ester transfer protein (CETP) activity has been reported in type 1 diabetic subjects and may contribute to their high incidence of macrovascular complications. LDL delivers arachidonic acid (AA), as cholesteryl ester (CE), to cells such as monocytes and fibroblasts as a precursor for eicosanoid synthesis. The authors found AA content in LDL CE was significantly correlated with CETP activity in type 1 diabetic children, even after controlling for CETP concentration. Production of leukotriene B4 (LTB4), a potent chemotactic and pro-inflammatory factor implicated in atherogenesis, is increased in type 1 diabetic patients. The authors hypothesize that increased CETP activity and transient hyperinsulinemia raise AA content in LDL CE, enhancing LTB4 synthesis and contributing to the higher cardiovascular disease incidence in these subjects.

CETP expression halves atherosclerotic lesion area in non-diabetic LDL-receptor-deficient mice, but this protection disappears with diabetes, another context-dependence finding for the CETP paradox (APMIS 2005)

Wed, 19 Aug 2026 20:56:25 +0200

The role of CETP expression and diabetes in atherogenesis was investigated in mice with heterozygous LDL receptor gene disruption (LDLR1). LDLR1 mice with and without CETP expression were treated with streptozotocin (STZ) and fed a standard diet for one month before switching to an atherogenic diet for another month. STZ-sensitive mice had roughly 2.5-fold higher glycemia and 7.5- to 8.0-fold higher cholesterolemia. Factorial analysis of variance showed no significant effect of diabetes, CETP, or their interaction on lesion size overall. However, CETP expression in non-diabetic mice produced a 50% reduction in lesion area. Triglyceridemia was an independent atherogenic risk factor in LDLR1 mice, and cholesterolemia in diabetic mice. CETP expression did not alter diabetes-driven lesion formation, but appeared protective in the euglycemic state.

In the Hoorn Study, high CETP concentration more than triples cardiovascular disease risk in women with Type 2 diabetes, with no such association in men (Diabet Med 2007)

Wed, 19 Aug 2026 20:56:23 +0200

The role of cholesteryl ester transfer protein (CETP) in atherogenesis remains unclear, so the authors studied the association of CETP concentration with cardiovascular disease (CVD) prevalence and carotid intima-media thickness (IMT) across normal glucose tolerance, impaired glucose tolerance, and Type 2 diabetes. Subjects (n=566) from the 2000-2001 Hoorn Study follow-up had CETP measured by immunoassay; CVD was defined by self-reported history or measured markers, and IMT by ultrasound. In men, CETP concentration was not associated with CVD regardless of glucose tolerance status. In women with normal or impaired glucose tolerance there was also no relationship, but in women with Type 2 diabetes, high CETP was associated with increased CVD risk (odds ratio 3.34 (1.56; 7.14)). No significant association was found between CETP and IMT in the whole cohort.

A four-week rimonabant intervention in CETP-humanised mice cuts body weight 9.4% and plasma cholesterol 24%, with systems-lipidomics revealing distinct plasma and liver lipid signatures (PLoS One 2011)

Wed, 19 Aug 2026 20:56:22 +0200

The anti-obesity drug rimonabant, a cannabinoid-1 receptor blocker, was previously used with diet and exercise in obese patients with risk factors like type 2 diabetes and dyslipidaemia, but its impact on early-obesity lipid metabolism in plasma and liver was less understood. The authors ran a four-week parallel controlled intervention in apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) transgenic mice with mild overweight and hypercholesterolemia, using mass spectrometry-based lipidomics. Rimonabant produced a significant 9.4% body weight loss and a significant 24% reduction in plasma total cholesterol. Six plasma and three liver lipids most significantly responded to treatment, with distinct lipid patterns between treated and untreated mice in both plasma and liver. Rimonabant modestly affected lipid metabolism and body weight in early-obesity ApoE*3Leiden.CETP mice.

Dietary cholesterol dose-dependently drives osteoarthritis in CETP-humanised mice, and atorvastatin but not ezetimibe suppresses it despite similar cholesterol lowering (Ann Rheum Dis 2013)

Wed, 19 Aug 2026 20:56:20 +0200

Hypercholesterolaemia, a risk factor for atherosclerosis (ATH), has been suggested to also contribute to osteoarthritis (OA). The authors tested cholesterol and cholesterol-lowering treatments in female ApolipoproteinE*3Leiden.human Cholesteryl Ester Transfer Protein mice, a model resembling human lipoprotein metabolism. Mice received a western-type diet with 0.1% cholesterol (LC), 0.3% cholesterol (HC), 0.3% cholesterol plus atorvastatin, or 0.3% cholesterol plus ezetimibe, with one group remaining on chow; knee OA grades and ATH extent were assessed after 39 weeks. LC and HC groups developed significantly more medial-side OA than controls, dose-dependently. Atorvastatin, but not ezetimibe, significantly suppressed OA, even though both similarly suppressed ATH features (48% and 55% respectively). OA correlated significantly with cholesterol exposure (r=0.4) and ATH features (r=0.3).

Across 6,606 adults and multiple imaging-based fat measures, no association is found between body fat and serum CETP, challenging the adipose-tissue-as-CETP-source hypothesis (Atherosclerosis 2016)

Wed, 19 Aug 2026 20:56:19 +0200

Adipose tissue has been proposed to contribute substantially to the serum cholesteryl ester transfer protein (CETP) pool, but a recent large cohort study found no association between waist circumference and plasma CETP. The authors further examined body-fat measures against serum CETP in the Netherlands Epidemiology of Obesity study. In 6,606 participants aged 45-65, total body fat, BMI, waist circumference, waist-to-hip ratio, and MRI-assessed abdominal and visceral adipose tissue (n=2547), plus DXA-assessed total and trunk fat mass (n=909), were examined against serum CETP, adjusting for age, ethnicity, sex, diet, activity, smoking and menopausal status. Mean serum CETP was 2.47 microgram/mL. Differences in serum CETP per SD of total body fat or BMI were both around the null (0.02 microgram/mL), with similarly null associations for all other adiposity measures, indicating adipose tissue does not contribute to the CETP pool in serum.

Neither a liraglutide RCT nor a 1,611-person cohort finds any link between liver fat content and circulating CETP, despite CETP's hepatic Kupffer-cell origin (Sci Rep 2019)

Wed, 19 Aug 2026 20:56:17 +0200

Cholesteryl ester transfer protein (CETP) is mainly expressed by Kupffer cells in the liver, and reducing hepatic triglyceride content (HTGC) with pioglitazone or caloric restriction has been shown to lower circulating CETP. Since GLP-1 analogues also reduce HTGC, the authors tested whether liraglutide decreases CETP, and separately examined the HTGC-CETP association in a population cohort. In a placebo-controlled trial, 50 patients with type 2 diabetes received liraglutide or placebo added to standard care; HTGC and CETP were also measured in 1,611 participants of the Netherlands Epidemiology of Obesity (NEO) study. HTGC decreased in both the liraglutide (-6.3%) and placebo (-4.0%) groups with no between-group difference, and CETP was not decreased by either liraglutide or placebo. No association was found between HTGC and CETP at baseline, after treatment, or in the cohort, indicating circulating CETP is not determined by hepatic triglyceride content.

A review commits to covering PCSK9, ANGPTL8, sortilin and CETP as candidate molecular links between psoriasis and cardiometabolic syndrome risk (Int J Mol Sci 2020)

Wed, 19 Aug 2026 20:48:56 +0200

Psoriasis is a systemic immune-metabolic disease with strong genetic predisposition and autoimmune features. Cardio-metabolic syndrome (CMS) is a leading comorbidity, occurring in 30-50% of psoriatic patients, and both conditions share pathways related mainly to proinflammatory signalling and cytokine profiles, though the exact mechanisms linking CMS to psoriasis remain incompletely understood. Drawing on recent clinical and basic-science findings, this review comprehensively discusses the roles of four proteins as plausible links between psoriasis and CMS: proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 8 (ANGPTL8), sortilin (SORT1), and cholesteryl ester transfer protein (CETP).

Four weeks of oral Akkermansia muciniphila lowers cholesterol and reshapes immune cell populations in CETP-humanised mice, but does not reduce cuff-induced neointima formation (Mol Nutr Food Res 2019)

Wed, 19 Aug 2026 20:48:55 +0200

Akkermansia muciniphila is an intestinal commensal bacterium with anti-inflammatory properties. The authors investigated the effects of oral A. muciniphila on lipid metabolism, immunity, and cuff-induced neointima formation in hyperlipidemic APOE*3-Leiden(E3L).CETP mice, a humanised model expressing human cholesteryl ester transfer protein. Male E3L.CETP mice received daily oral A. muciniphila (2 x 10^8 CFU) for 4 weeks. Treatment lowered body weight and plasma total cholesterol and triglycerides, increased the total B cell population while reducing total T cell and neutrophil populations in mesenteric lymph nodes, and reduced expression of the activation markers MHCII on dendritic cells and CD86 on B cells. A. muciniphila also increased whole-blood ex vivo LPS-stimulated IL-10 release, but despite improving lipid metabolism and immunity, did not affect neointima formation or composition.

Unlike three other newly identified EGPA biomarkers, CETP is selectively downregulated and negatively correlates with eosinophil count, aiding diagnosis versus severe asthma (Front Immunol 2022)

Wed, 19 Aug 2026 20:48:53 +0200

Eosinophilic granulomatosis with polyangiitis (EGPA) presents with asthma-like attacks and is easily misdiagnosed as severe asthma, so new early-diagnosis biomarkers are needed. Data-independent acquisition (DIA) proteomics screened biomarkers in 45 healthy controls, severe asthma and EGPA patients, with parallel reaction monitoring (PRM) validating findings in 71 further patients. Four candidate biomarkers were identified: serum amyloid A1 (SAA1), fibrinogen-alpha (FGA) and serum amyloid P component (SAP) were upregulated in EGPA, while cholesteryl ester transfer protein (CETP) was downregulated in EGPA compared with severe asthma. Combining SAA1, FGA and SAP gave an AUC of 0.947 (82.35% sensitivity, 100% specificity) for early EGPA diagnosis, while adding CETP gave an AUC of 0.921 (78.13% sensitivity, 100% specificity) for differentiating EGPA from severe asthma. SAA1, FGA and SAP correlated positively, and CETP negatively, with eosinophil count.

Combined GIPR/GLP1R agonism additively lowers triglycerides, hepatic steatosis and Kupffer-cell-driven liver inflammation in CETP-humanised NAFLD mice (EBioMedicine 2023)

Wed, 19 Aug 2026 20:48:52 +0200

Combined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism outperforms GLP1R agonism alone for glycemic control and weight loss in obesity. The authors tested combined GIPR/GLP1R agonism against nonalcoholic fatty liver disease (NAFLD) in male APOE∗3-Leiden.CETP mice, a humanised model of diabetic dyslipidemia and NAFLD, fed a high-fat high-cholesterol diet and injected every other day with vehicle, a GIPR agonist, a GLP1R agonist, or both combined. GIPR and GLP1R agonism reduced body weight and additively lowered fasting glucose, triglycerides and total cholesterol. Combined treatment additively reduced hepatic steatosis, evidenced by lower hepatic lipid content and NAFLD scores, driven by reduced food intake, reduced intestinal lipid absorption, and increased brown-adipose-tissue uptake of glucose and fatty acids. Combined agonism also attenuated hepatic inflammation, shown by fewer monocyte-derived Kupffer cells and lower inflammatory-marker expression, alongside reduced markers of liver injury.

A four-protein urinary panel including CETP, combined with tumor diameter and AFP/GGT levels, predicts microvascular invasion in liver cancer with concordance indices up to 0.809 (BMC Med 2023)

Wed, 19 Aug 2026 20:42:46 +0200

Microvascular invasion (MVI) is the main prognostic factor in hepatocellular carcinoma (HCC). The authors conducted label-free quantitative proteomic studies on urine from 91 HCC patients and 22 healthy controls to identify preoperative biomarkers predicting MVI status. Urinary proteomic features of healthy controls reflected active metabolic processes, while the HCC group showed pathways related to cell adhesion and proliferation, including extracellular matrix organization and cell-cell junction organization. Using expression levels of four urinary proteins, cholesteryl ester transfer protein (CETP), HGFL, L1CAM and LAIR2, combined with tumor diameter, serum AFP and GGT concentrations, the authors built a preoperative nomogram predicting MVI status, achieving concordance indexes of 0.809 in the training cohort and 0.783 in an independent testing cohort (n=23), confirmed by ELISA in a further validation cohort (n=57).

Unlike LBP, its structural relatives BPI, CETP and PLTP show no expression difference in necrotizing enterocolitis, isolating LBP as the disease-associated biomarker (J Pediatr Surg 2026)

Wed, 19 Aug 2026 20:42:44 +0200

This study aimed to identify lipopolysaccharide-binding protein (LBP) as a diagnostic biomarker for necrotizing enterocolitis (NEC), a life-threatening neonatal gastrointestinal disease, using multi-omics analysis of intestinal tissue integrated with a public dataset (GSE46619). LBP protein was significantly upregulated in NEC versus controls, increasing with disease severity, and correlated strongly with inflammatory cytokines IL-6 and IL17RA. In contrast, other LBP-related proteins, BPI, cholesteryl ester transfer protein (CETP) and PLTP, showed no significant difference between NEC and controls. LBP correlated positively with CRP and negatively with lymphocyte count, and achieved an area under the curve of 0.8252 for diagnosing NEC (64.1% sensitivity, 90.91% specificity), rising to 0.9702 for stage III disease. Combining LBP with CRP improved diagnostic AUC to 0.8834.

Chromatography, electrophoresis and immunoprecipitation together show apolipoprotein D and CETP are distinct proteins, resolving early confusion about CETP's identity (Biochim Biophys Acta 1981)

Wed, 19 Aug 2026 20:36:35 +0200

This study addressed whether cholesteryl ester transfer protein (CETP) and apolipoprotein D are identical. The two proteins did not co-purify during hydrophobic and cationic exchange chromatography and were readily separated by molecular sieve chromatography or electrophoresis. Furthermore, precipitating apolipoprotein D with specific antisera did not diminish the transfer activity of lipoprotein-deficient plasma. The authors conclude apolipoprotein D and cholesteryl ester transfer protein have significantly different physicochemical properties.

HepG2 human liver cells synthesize and secrete a protein immunochemically identical to plasma LTP-I, identifying hepatocytes as a candidate source (Arteriosclerosis 1987)

Wed, 19 Aug 2026 20:36:33 +0200

The authors examined the synthesis, secretion, and functional and physical characteristics of a lipid transfer protein synthesized by a human hepatocellular carcinoma line. This protein shared immunochemical determinants and many other properties with the lipid transfer protein, LTP-I, previously purified from human plasma. The authors conclude the human liver cell line HepG2 synthesizes and secretes LTP-I, indicating hepatocytes may be the source of LTP-I in human plasma.

The original isolation of the 74kDa human plasma CETP reveals a leucine-rich, highly hydrophobic protein specific for cholesteryl ester over triglyceride transfer (Proc Natl Acad Sci U S A 1987)

Wed, 19 Aug 2026 20:36:32 +0200

The authors isolated a cholesteryl ester transfer protein from human plasma whose ligand specificity, molecular weight and amino acid composition differed significantly from proteins previously reported to have this activity. Purified about 100,000-fold from plasma, the protein is rich in hydrophobic amino acids, especially leucine, with a molecular weight of 74,000 and an isoelectric point of 5.2. Its transfer rate for cholesteryl ester was similar between each major plasma lipoprotein class and rapid compared with triacylglycerol transfer, regardless of the donor and acceptor lipoproteins' overall lipid composition. The authors conclude this protein functions primarily in transferring cholesteryl esters between plasma lipoproteins.

Neutralizing antibodies against the 74kDa CETP eliminate essentially all plasma cholesteryl ester and triglyceride transfer activity, proving CETP is the responsible protein (J Biol Chem 1988)

Wed, 19 Aug 2026 20:36:30 +0200

A cholesteryl ester transfer protein (CETP) of apparent Mr 74,000 had recently been purified from human plasma. The authors obtained three monoclonal neutralizing antibodies to CETP by immunizing mice with the purified protein. Each antibody, recognizing a similar CETP epitope, caused parallel and complete immunotitration of plasma cholesteryl ester and triglyceride transfer activities, but only partial inhibition of phospholipid transfer activity. Monoclonal immunoaffinity chromatography of plasma or its fractions completely removed cholesteryl ester and triglyceride transfer activities but only incompletely removed phospholipid transfer activity. SDS gel electrophoresis and immunoblotting of the immunoaffinity-retained fractions showed only the Mr 74,000 protein was immunoreactive. The previously characterized CETP thus accounts for all cholesteryl ester and triglyceride transfer activity in human plasma, but only part of the phospholipid transfer activity.

CaCo-2 enterocytes secrete CETP (LTP-I) exclusively from their basolateral surface at twice the rate of HepG2 cells, and uniquely regulate secretion by fatty acid levels (J Biol Chem 1988)

Wed, 19 Aug 2026 20:30:39 +0200

The authors investigated the human CaCo-2 enterocyte model for secretion of plasma cholesteryl ester transfer protein, LTP-I. CaCo-2 cells secrete a cholesteryl ester transfer protein with molecular identity to plasma LTP-I, shown by anti-LTP-I immunoblot analysis and immunoinhibition of all cell-secreted transfer activity. When cultured on permeable membranes, CaCo-2 cells showed cholesteryl ester transfer activity only in the lower culture compartment, demonstrating vectorial sorting and secretion of LTP-I, like the intestinal apolipoproteins, from the basolateral domain. Over 24 hours, CaCo-2 cells secreted cholesteryl ester transfer activity at roughly twice the rate of HepG2 cells. Unlike HepG2 hepatocytes, CaCo-2 enterocytes regulated LTP-I secretion in response to fatty acid concentration in the culture medium.

HepG2 hepatocytes secrete CETP activity bound mainly to apoA-I and apoA-II, unlike plasma's strong apoA-I skew, alongside a distinct heat-labile lipid-transfer inhibitor tied to apoE particles (Atherosclerosis 1989)

Wed, 19 Aug 2026 20:30:38 +0200

Using immunoaffinity chromatography, the authors characterized the distribution of cholesteryl ester transfer activity in particles secreted by HepG2 hepatocytes. HepG2-secreted cholesteryl ester transfer activity was associated with apolipoprotein (apo) A-I (58%) and apo A-II (55%), but not apo B or apo E. This contrasts with human plasma, where the authors' previous studies showed most (88%) transfer activity is associated with apo A-I and very little (7%) with apo A-II, suggesting the plasma distribution reflects active remodeling of nascent particles after secretion. The authors also found HepG2 cells secrete a lipid transfer inhibitor activity associated with apo E-containing lipoprotein particles, which was heat labile.

CETP retains lipid-transfer activity after protease fragmentation but not as isolated E. coli-expressed fragments, showing no independent catalytic subunit exists (J Biol Chem 1989)

Wed, 19 Aug 2026 20:30:36 +0200

To define an active domain of cholesteryl ester transfer protein (CETP), the authors generated protein fragments by limited digestion of native plasma-derived CETP with trypsin, chymotrypsin or Staphylococcus aureus V8 protease, and separately expressed CETP cDNA restriction fragments in Escherichia coli. Trypsin or chymotrypsin digestion extensively fragmented CETP and eliminated the intact 74-kDa molecule, yet cholesteryl ester (CE) transfer activity was unaffected; V8 protease treatment only partially reduced activity. Molecular sieve chromatography showed the CE-transfer-active proteolytic product consisted of associated polypeptide fragments retaining CETP's native molecular weight, resistant to dissociation by dithiothreitol, 8 M urea, or delipidating agents. In contrast, CETP polypeptides from bacterially expressed cDNA fragments, and selected synthetic CETP peptides, were catalytically inactive. No evidence was found for an independently active CETP subunit; CETP requires a distinct, highly stable tertiary structure for catalytic activity.

Within three days, an atherogenic diet raises rabbit liver CETP mRNA 2.8-fold and plasma CETP mass 3.2-fold, while other liver mRNAs stay unchanged (J Clin Invest 1990)

Wed, 19 Aug 2026 20:30:35 +0200

Cholesteryl ester transfer activity rises in plasma of cholesterol-fed rabbits, and the authors investigated the mechanism by measuring cholesteryl ester transfer protein (CETP) mass by radioimmunoassay and CETP mRNA by Northern and slot blot analysis in control (n=8) and cholesterol-fed (n=10) rabbits. Thirty days of cholesterol feeding (chow plus 0.5% cholesterol, 10% corn oil) increased plasma CETP mass 3.2-fold (12.45 +/- 0.82 vs 3.86 +/- 0.38 micrograms/ml), and liver CETP mRNA rose 2.8-fold, while actin, apoE, lecithin-cholesterol acyltransferase and albumin mRNA were unchanged. Unlike the widespread human tissue distribution, CETP mRNA was undetectable in extrahepatic tissue of either group. A sensitive RNase protection assay detected the liver CETP mRNA increase within 3 days of starting the diet, an early, gene-specific response to dietary cholesterol.

Doubling plasma CETP activity via diet does not speed cholesteryl ester clearance from hepatic reticuloendothelial cells in hamsters (Biochim Biophys Acta 1991)

Wed, 19 Aug 2026 20:30:33 +0200

The putative role of cholesteryl ester transfer protein (CETP) in removing cholesteryl ester from hepatic reticuloendothelial cells in vivo was studied in hamsters, using retention of the nonhydrolysable cholesteryl ester analog [3H]cholesteryl linoleyl ether ([3H]CLE) after injecting [3H]CLE-labeled acetylated LDL, which targets nonparenchymal littoral cells. In chow-fed hamsters, plasma cholesteryl ester transfer activity (CETA) was 10.6 +/- 0.9 units, and 28-day hepatic [3H]CLE retention was 86% of the 4-hour value, versus about 55% in rats, in which CETA was undetectable. Supplementing the diet with 2% cholesterol and 15% margarine doubled hamster CETA, yet hepatic [3H]CLE retention at 28 days was unchanged; dietary fat supplementation also did not change retention in rats. These results do not support a role for CETP in vivo in removing cholesteryl ester from intact reticuloendothelial cells.

Baculovirus-expressed CETP deletion mutants pinpoint residues Phe-Leu-Leu-Leu (454-457) as essential for lipid transfer, a motif shared with LCAT, LBP, BPI and other lipid-binding enzymes (Proc Natl Acad Sci U S A 1992)

Wed, 19 Aug 2026 20:30:31 +0200

Functional plasma cholesteryl ester transfer protein (CETP; 476 amino acids) was expressed in baculovirus-transfected Sf9 insect cells using a full-length cDNA from a human placental library. The product bound each major plasma lipoprotein class and catalyzed transfer of both cholesteryl esters and triglyceride. CETP species with overlapping carboxyl-terminal deletions were defective in cholesteryl ester and triglyceride transfer. Structural and functional analysis suggested normal lipoprotein binding and catalysis require the carboxyl-terminal sequence -Phe-Leu-Leu-Leu- (residues 454-457). A similar sequence occurs in several other nonpolar-lipid-binding proteins, including lecithin:cholesterol acyltransferase, lipopolysaccharide-binding protein, bactericidal permeability-increasing protein, cholesterol 7 alpha-hydroxylase, cholesterol esterase, and hormone-sensitive lipase, suggesting a conserved neutral lipid-binding sequence may be important for CETP and other lipid-metabolism proteins.

A monoclonal antibody that blocks CETP's triglyceride transfer but not cholesteryl-ester transfer suggests the two lipids use distinct binding sites (J Biochem 1992)

Wed, 19 Aug 2026 20:24:16 +0200

Plasma cholesteryl ester transfer protein (CETP) facilitates net transfer and exchange of cholesteryl ester (CE), triglyceride (TG) and phospholipids between lipoproteins. The authors raised a series of monoclonal antibodies (mAbs) against human CETP, comprising mAbs that either inhibited or did not inhibit its transfer activities. One mAb, LT-J1, inhibited TG transfer activity almost completely but not CE transfer, suggesting the CE and TG binding sites on CETP may be distinct and that this mAb specifically recognizes the TG binding site. The authors also established a radioimmunoassay for CETP levels using these mAbs, finding plasma CETP levels in 20 normolipemic Japanese adults ranged from 2.1 to 2.7 mg/liter.

Deletion mutagenesis pinpoints residues Phe463 to Leu475 as essential for both TP2 antibody binding and CETP's neutral-lipid-transfer activity (J Biol Chem 1992)

Wed, 19 Aug 2026 20:24:15 +0200

Cholesteryl ester transfer protein (CETP; 476 amino acids) mediates neutral lipid and phospholipid transfer between plasma lipoproteins. The epitope of the neutralizing monoclonal antibody TP2 was previously shown to lie within CETP's C-terminal 26 amino acids. To probe this region's role in lipid transfer, the authors generated six deletion mutants between Arg451 and Leu475 and expressed them in mammalian cells. Only deletion mutants spanning Phe463 to Leu475 failed to bind TP2; these mutants were well secreted but showed markedly reduced cholesteryl ester transfer activity. One deletion mutant (delta470-475) showed similarly reduced cholesteryl ester and triglyceride transfer but normal or increased phospholipid transfer, with limited proteolysis indicating a folding pattern resembling wild type. Residues between Phe463 and Leu475 are thus necessary for TP2 binding, and deletions here selectively impair neutral lipid transfer.

C/EBP binds the CETP gene promoter and boosts its reporter-gene activity in liver cells, with C/EBP and CETP mRNA loss occurring in parallel in cultured hepatocytes (J Biol Chem 1992)

Wed, 19 Aug 2026 20:24:13 +0200

Plasma cholesteryl ester transfer protein (CETP), synthesized mainly in the liver, is expressed at very low levels in transformed human liver cell lines. The human CETP gene promoter contains a sequence closely resembling the binding site for transcription factor CCAAT/enhancer-binding protein (C/EBP), confirmed to bind C/EBP by electrophoretic mobility shift and DNase I footprint analyses. A bacterial chloramphenicol acetyltransferase (CAT) reporter under the human CETP promoter showed low activity in the HepG2 human hepatoma line, but activity was markedly elevated in the presence of C/EBP. In primary hepatocyte cultures, CETP mRNA was lost rapidly in parallel with C/EBP mRNA. C/EBP may thus maintain CETP gene promoter activity, and its low levels in proliferating or cultured cells may explain the low CETP expression seen in immortalized liver cell lines or cultured hepatocytes.

Bulky hydrophobic residues Leu475, Phe471, Leu468, Phe461 and Phe454 on one face of a C-terminal helix drive CETP's cholesteryl-ester transfer activity, distinct from the antibody-binding face (J Biol Chem 1993)

Wed, 19 Aug 2026 20:24:12 +0200

A carboxyl-terminal CETP sequence forms the epitope of the neutralizing monoclonal antibody TP2 and is required for neutral lipid transfer activity. To dissect individual residues' roles, the authors made single amino acid substitution mutants between Pro446 and Ser476 and expressed them in mammalian cells. TP2 binding was abolished by mutations of polar or charged residues occurring periodically between His466 and Leu475 and at Asp460, yet these mutants retained well-preserved cholesteryl ester (CE) transfer activity. In contrast, mutating bulky hydrophobic residues in this region (particularly Leu475, Phe471, Leu468, Phe461 and Phe454) markedly decreased CE transfer activity while preserving normal TP2 binding. This paradox fits a model placing antibody-binding and activity-determining residues on opposite faces of an amphipathic helix between residues 465-476, confirmed by alanine substitution of contiguous nonpolar residue pairs, producing low-activity mutants matching deletions of this region.

CHO-cell expression and site-directed mutagenesis show all four potential N-glycosylation sites of CETP are occupied, explaining its glycoprotein doublet on SDS gels (Biochemistry 1993)

Wed, 19 Aug 2026 20:24:10 +0200

Plasma cholesteryl ester transfer protein (CETP) mediates neutral lipid and phospholipid transfer between lipoproteins. Its cDNA predicts a 53,000 Da polypeptide, but plasma CETP runs as a broad SDS-gel band of two forms at 65,000-71,000 Da. The authors tested whether variable N-linked glycosylation explains this microheterogeneity. Recombinant CETP (rCETP) from stable CHO-cell expression appeared as a doublet like plasma CETP. Digesting plasma or rCETP with N-glycosidase F produced a lower-molecular-weight doublet, the bottom band approximating the bare polypeptide mass. Metabolic labeling suggested the doublet's top band retained glyco-F-resistant N-linked carbohydrate. Mutating each of CETP's four potential N-linked glycosylation sites (asparagine 88, 240, 341 and 396, to glutamine) individually showed every mutant had a lower molecular weight than wild type, indicating all four sites carry N-linked carbohydrate.

A new self-quenching BODIPY-cholesteryl-ester microemulsion assay enables simple fluorescence-based measurement of CETP activity in plasma (J Lipid Res 1993)

Wed, 19 Aug 2026 20:17:55 +0200

The authors describe a simple, practical method to assess cholesteryl ester transfer protein (CETP) activity in a defined system, using microemulsions containing a fluorescent cholesteryl ester analog. The microemulsions are stable, simple to prepare, and can be made to defined composition, with initial transfer rates easily determined by monitoring fluorescence changes. Using the fluorescent analog BODIPY-CE, which self-quenches in a concentration-dependent manner when incorporated into microemulsions, the authors demonstrated fluorescent lipid transfer facilitated by rabbit and human d greater than 1.21 g/ml plasma fraction and by recombinant human CETP. A known inhibitory monoclonal antibody to human CETP blocked BODIPY-CE transfer dose-dependently. The assay was also used to measure CETP activity directly in whole plasma.

N-linked glycosylation, not the N-terminal cysteine, proves essential for CETP lipid-transfer activity in a new Pichia pastoris recombinant expression system (J Lipid Res 1996)

Wed, 19 Aug 2026 20:17:53 +0200

Rabbit cholesteryl ester transfer protein (CETP) was expressed in the methylotrophic yeast Pichia pastoris via a methanol-inducible promoter. The cloned cDNA differed from the previously published sequence at six residues, five of which matched the corresponding human CETP residues, and the mature N-terminal sequence was changed from Cys- to Arg-Glu-Phe- to link CETP to the yeast signal peptide. Culture medium from methanol-induced cells showed cholesteryl ester and triglyceride transfer activity comparable to rabbit plasma, inhibitable by monoclonal antibodies as in native plasma, with specific transfer activity indistinguishable from plasma CETP despite molecular weight differences. N-Glycosidase F treatment converted both recombinant and plasma CETP to a single 55 kDa species and abolished activity in both. Recombinant CETP is thus synthesized as an inactive polypeptide processed into a functional glycoprotein, and the N-terminal cysteine is not required for activity.

Antibodies raised against CETP residues 131-142 can immunoprecipitate CETP activity from serum without inhibiting the enzyme, marking a non-active-site epitope (Hybridoma 1996)

Wed, 19 Aug 2026 20:17:52 +0200

A synthetic peptide corresponding to residues 131-142 of human cholesteryl ester transfer protein (CETP) was used as an immunogen to raise monoclonal antibodies (MAbs) specific for the intact CETP molecule. Spleen cells from immunized BALB/c mice were fused with SP2/0 myeloma cells, yielding two MAbs, ATM192 (IgG1) and J16-14 (IgG3), that bound peptide by ELISA and were used in Western blotting. Immunoprecipitation with ATM192 removed CETP enzyme activity from human serum without destroying the enzyme's activity, and both antibodies bound CETP from rabbits. Specificity studies and the lack of enzymatic inhibition suggest the MAbs bind a structural region of CETP outside the active binding site, useful for measuring CETP levels in human serum and rabbit or human tissue homogenates.

A novel transposon-based method sequences 5kb of CETP's 5' regulatory region, revealing a 5.7kb fragment drives far stronger transcription than the minimal promoter (Gene 1997)

Wed, 19 Aug 2026 20:17:50 +0200

The authors isolated and sequenced genomic clones spanning more than 5 kb of the 5' flanking region of the cholesteryl ester transfer protein (CETP) gene. This region contains multiple Alu repeats, a Mermaid repeat, and an extensive GA repeat that made conventional sequencing exceedingly difficult, so the authors employed a novel transposon-facilitated technique using the artificial transposon AT-2, which integrated efficiently across the entire region of interest. Sequence analysis revealed multiple potential regulatory factor binding sites upstream of the previously characterized minimal promoter. The 5.7-kb regulatory region conferred significantly greater transcriptional activation in a conditionally transformed mouse hepatocyte line than a minimal 137-bp promoter fragment. A variable-length tetranucleotide repeat, potentially useful as a genetic marker, was identified 2 kb upstream of the CETP transcriptional start site.

CETP mRNA is 96% higher in the immature stromal-vascular fraction of human fat tissue than in mature adipocytes, unlike lipoprotein lipase or apoE (Biochim Biophys Acta 1998)

Wed, 19 Aug 2026 20:12:00 +0200

Cholesteryl ester transfer protein (CETP) mRNA is more abundant in small mature adipocytes than in large, lipid-rich adipocytes. The authors isolated the stromal vascular fraction (SVF) of human adipose tissue and confirmed the presence of very small fat cells within it. Northern blot analysis showed CETP mRNA expression was significantly greater (+96%, P<0.03) in stromal-vascular cells (SVC) than mature fat cells, whereas lipoprotein lipase mRNA was lower (-75%, P<0.03) in SVC and apolipoprotein E mRNA did not differ significantly. RT-PCR showed CETP mRNA was expressed by human pre-adipocytes at levels below those of SVC and adipocytes, and the absence of FcgammaRIII (CD16) mRNA confirmed SVC lacked monocytes/macrophages. CETP mRNA is thus most highly expressed in the immature fat cells of human adipose tissue, consistent with CETP playing an important local role in adipocyte cholesterol accumulation.

Erabulenols A and B, new fungal metabolites from a soil Penicillium isolate, inhibit human CETP with IC50 values of 47.7 and 58.2 micromolar (J Antibiot (Tokyo) 1998)

Wed, 19 Aug 2026 20:11:58 +0200

Penicillium sp. FO-5637, a soil isolate, was found to produce a series of cholesteryl ester transfer protein (CETP) inhibitors. Novel active compounds, erabulenols A and B, were isolated from the fermentation broth by solvent extraction, ODS column chromatography and HPLC. Erabulenols A and B inhibited human CETP activity with IC50 values of 47.7 and 58.2 microM, respectively, in an in vitro assay system containing 200 microM BSA.

Erabulenols A and B, fungal CETP inhibitors, share a phenalenone-tetrahydrofuran core, with a hydroxy-methylketonyl benzyl group distinguishing erabulenol B (J Antibiot (Tokyo) 1998)

Wed, 19 Aug 2026 20:11:56 +0200

The structures of erabulenols A and B, novel fungal inhibitors of cholesteryl ester transfer protein, were elucidated by spectroscopic studies including various NMR measurements. Erabulenols share a phenalenone skeleton and a 1,2,2-trimethyltetrahydrofuran moiety in common. Erabulenol B additionally possesses a 2,6-dihydroxy-5-methyl-3-methylketonyl benzyl moiety. The absolute stereochemistry at the C-2' position of erabulenol A was deduced as S by comparison of its optical rotation with related compounds.

Modeled on BPI's crystal structure, a proposed CETP mechanism has C-terminal residues 461-476 forming a helix that gates lipid entry into a hydrophobic pocket (Curr Opin Struct Biol 1998)

Wed, 19 Aug 2026 20:11:55 +0200

Cholesteryl ester transfer protein (CETP) is evolutionarily related to bactericidal/permeability-increasing protein (BPI). The recently solved BPI crystal structure revealed an elongated, boomerang-shaped molecule with two hydrophobic pockets opening to its concave side, each containing a phospholipid molecule. The authors built a model of CETP based on this BPI structure to interpret CETP functional studies. In this model, C-terminal residues 461-476, previously shown required for neutral lipid transfer between plasma lipoproteins, form an amphipathic helix covering the opening of the N-terminal pocket. Drawing on this structural model, the authors propose a lipid-transfer mechanism for CETP in which lipids in the lipoprotein surface are first disordered, then a lipid molecule flips and enters the hydrophobic lipid-binding pocket.

A review by the LTIP discoverer surveys how CETP expression, atherogenesis and lipid transfer inhibitor protein activity interconnect (Curr Opin Lipidol 1999)

Wed, 19 Aug 2026 20:11:53 +0200

This review examines the interconnections between cholesteryl ester transfer protein (CETP) expression and lipid metabolism, and the possible roles of CETP in atherogenesis. The importance of lipid transfer inhibitor protein (LTIP) in modulating CETP activity is detailed, along with the proposed consequences of this inhibitory activity on CETP-mediated events.

A refined CETP epitope map, built from eight monoclonal antibody binding sites, supports a BPI-based structural model of CETP's overall conformation (Protein Sci 1999)

Wed, 19 Aug 2026 20:11:51 +0200

Cholesteryl ester transfer protein (CETP) belongs to a gene family that also includes bactericidal/permeability-increasing protein (BPI), whose crystal structure reveals two domains sharing a similar fold with an apolar ligand-binding pocket; conserved structurally important residues suggest CETP may share BPI's overall conformation. Building on a previous CETP structural model based on anti-CETP monoclonal antibody (mAb) binding, the authors present a refined epitope map adapted to a structural model using BPI's atomic coordinates. Four epitopes (CETP residues 215-219, 219-223, 223-227 and 444-450) are predicted on the external surface of the central beta-sheet, a fifth (225-258) on the interdomain linker, and three others (317-331, 360-366, 393-410) on the putative carboxy-terminal beta-barrel. The ability of corresponding mAbs to compete for CETP binding matched the predicted proximity of their epitopes in the model, supporting CETP and BPI sharing similar surface topologies.

Human CETP overexpression in hypertensive Dahl rats spontaneously causes combined hyperlipidemia, myocardial infarction and reduced survival, proving CETP can be proatherogenic (Nat Med 1999)

Wed, 19 Aug 2026 20:06:27 +0200

The acceleration of atherosclerosis by polygenic hypertension is well characterised in humans, but a lack of animal models simulating this disease has hindered mechanistic study. The authors created a transgenic atherosclerosis-polygenic-hypertension model, Dahl salt-sensitive hypertensive rats overexpressing human cholesteryl ester transfer protein (Tg[hCETP]DS). Male Tg[hCETP]DS rats fed regular chow spontaneously developed age-dependent severe combined hyperlipidemia, atherosclerotic lesions, myocardial infarctions and decreased survival. These findings differed from various mouse atherosclerosis models, demonstrating the need for complex disease modeling across species. The data show cholesteryl ester transfer protein can be proatherogenic, and the interaction of polygenic hypertension and hyperlipidemia in Tg[hCETP]DS rats substantiates epidemiological observations in humans.

Ferroverdins B and C, natural CETP inhibitors from Streptomyces, are elucidated as iron complexes of nitroso-hydroxybenzoate ligands (J Antibiot (Tokyo) 1999)

Wed, 19 Aug 2026 20:06:25 +0200

The structures of ferroverdins B and C, novel inhibitors of cholesteryl ester transfer protein produced by Streptomyces sp. WK-5344, were elucidated by spectroscopic studies including various NMR measurements. Both compounds are complexes of one Fe2+ ion with three ligands: ferroverdin B comprises two common p-vinylphenyl-3-nitroso-4-hydroxybenzoates and one hydroxy p-vinylphenyl-3-nitroso-4-hydroxybenzoate, while ferroverdin C comprises one carboxylic acid p-vinylphenyl-3-nitroso-4-hydroxybenzoate in place of the hydroxy ligand.

Feeding, not fasting, raises liver CETP mRNA two-fold and plasma CETP activity 20% in human-CETP transgenic mice, independent of insulin or glucose (J Nutr Biochem 2000)

Wed, 19 Aug 2026 20:06:23 +0200

Cholesteryl ester transfer protein (CETP) is a potential atherosclerosis drug target whose regulation, possibly by insulin, remains under study. The authors compared CETP expression in transgenic mice carrying the human CETP minigene after 12 hours of fasting (n = 20) or ad libitum feeding (n = 20). Plasma cholesteryl ester transfer activity (CETA) was 20% higher in fed than fasted mice (P < 0.05), reflecting higher CETP levels, accompanied by 100% higher liver mRNA and 23% higher CETA and 29% higher CETP mass (all P < 0.05) in the liver particulate fraction. These liver parameters correlated well with each other and with plasma CETA. Liver particulate CETP appeared as a 70/65 kDa doublet resolving to a single approximately 60 kDa band upon deglycosylation. No fasting-fed differences were seen in adipose CETP, and neither insulin nor glucose correlated with any CETP parameter.

In a 24-week RCT, French-press coffee raises CETP activity up to 18% within two weeks, preceding the later rise in LDL cholesterol (J Intern Med 2000)

Wed, 19 Aug 2026 20:06:22 +0200

The authors examined the long-term effects of unfiltered coffee on cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP) and lecithin:cholesterol acyltransferase (LCAT) activity, and whether CETP contributes to coffee-induced LDL cholesterol rises. Forty-six healthy normolipidaemic subjects drank 0.9 L daily of French-press or filtered coffee for 24 weeks, with blood sampled at 0, 2, 12 and 24 weeks and after 12 weeks of follow-up. Relative to baseline, French-press coffee significantly raised average CETP activity by 12% after 2 weeks, 18% after 12 weeks, and 9% after 24 weeks; PLTP activity rose 10% after 12 and 24 weeks, while LCAT activity fell 6% after 12 weeks and 7% after 24 weeks. The CETP rise clearly preceded the rise in LDL cholesterol, though not the rise in triglycerides, and remained persistently elevated while the triglyceride rise was transient. Cafestol and kahweol in coffee thus cause a long-term rise in CETP and PLTP activity, which may contribute to the LDL cholesterol rise.

Cys-13, positioned near CETP's neutral-lipid-binding site, is identified as essential for irreversible inhibitor binding via mutagenesis and mass spectrometry (J Lipid Res 2000)

Wed, 19 Aug 2026 20:06:20 +0200

SC-71952, a substituted analog of dithiobisnicotinic acid dimethyl ester, was identified as a potent CETP inhibitor, with 1 micromolar required for half-maximal inhibition in vitro. Preincubating the inhibitor with CETP enhanced its potency 200-fold, while dithiothreitol treatment decreased it 50-fold; analogs lacking a disulfide linkage were less potent and unaffected by dithiothreitol. SC-71952 was found to first bind rapidly and reversibly to a hydrophobic CETP site, then irreversibly inactivate CETP by reacting with a free cysteine. LC/MS analysis of tryptic digests showed the Cys143-Cys184 disulfide bond was unaffected, but inactivation correlated with progressive loss of free Cys-13 and Cys-333. Mutating Cys-13 to alanine abolished the time-dependent potency enhancement seen with wild-type CETP, though not the rapid reversible component, identifying Cys-13 as critical for irreversible inactivation near CETP's neutral-lipid-binding site.

Immunohistochemistry and in situ hybridization localize CETP production to smooth muscle cells within the human aortic intima and media (Atherosclerosis 2001)

Wed, 19 Aug 2026 20:06:19 +0200

Cholesteryl ester transfer protein (CETP) is thought to mediate cholesteryl ester transfer from the arterial wall, but its distribution and production within human arterial wall were unclear. Using immunohistochemistry and in situ hybridization, the authors mapped CETP and CETP mRNA in human aortic wall. CETP was constantly distributed in the media, and also recognized within fibrocellular-thickened and atherosclerotic intima. Double immunostaining showed CETP expression in smooth muscle cells of the intima and media, and CETP mRNA was detected in both intimal and medial smooth muscle cells. Intimal cells expressing CETP mRNA were identified as monocyte-derived macrophages and smooth muscle cells, using antibodies against smooth muscle actin and human macrophage on serial sections. CETP is produced by smooth muscle cells in the intima and media of human aorta, suggesting they participate in removing excess cholesteryl ester from the arterial wall.

Replacing a tetrafluoroethoxy group with 2-furyl heteroaryl moieties yields submicromolar CETP inhibitors in a new trifluoro-propanol series (Bioorg Med Chem Lett 2001)

Wed, 19 Aug 2026 20:00:07 +0200

The authors prepared a series of novel N,N-disubstituted trifluoro-3-amino-2-propanols as potent inhibitors of cholesteryl ester transfer protein (CETP). Modifying the aromatic 3-tetrafluoroethoxy group in the lead molecule 1a with various heteroaryl moieties produced new 2-furyl analogues, compounds 2a and 2b, which showed submicromolar potency in vitro.

AICAR lowers blood glucose and insulin by suppressing endogenous glucose production, without correcting dyslipidaemia, in diabetic CETP-expressing KKAy mice (Diabetologia 2001)

Wed, 19 Aug 2026 20:00:05 +0200

5-aminoimidazole-4-carboxy-amide-1-beta-D-ribofuranoside (AICAR) increases 5-AMP-activated kinase activity in insulin-sensitive tissues controlling glucose homeostasis. The authors tested acute and 7-day AICAR treatment (100, 300, or 500 mg/kg/day) in female KKAy-CETP mice, a Type II diabetes model expressing human CETP. After 7 days at 500 mg/kg/day, blood glucose and plasma insulin were reduced (p < 0.01), as were body weight and food intake (p < 0.01 and p < 0.05); glucose and insulin tolerance improved (p < 0.05) while endogenous glucose production was suppressed (p < 0.05), with skeletal-muscle glucose uptake unaffected. However, plasma free fatty acids rose 1.9-fold (p < 0.01) and triglycerides rose 1.3-fold (p < 0.05). AICAR thus attenuated hyperglycaemia and hyperinsulinaemia but not dyslipidaemia in this CETP-expressing diabetes model.