HDL biology
In Tangier disease, CETP activity drives an LDL-triglyceride buildup on top of near-total HDL loss, a four-patient case series shows (J Clin Endocrinol Metab 2025)
Original title: Lipid Dysregulation in Tangier Disease: A Case Series and Metabolic Characterization
A multicentre case series characterised lipid metabolism in four patients with Tangier disease, a rare autosomal recessive disorder of cellular cholesterol export causing peripheral cholesterol accumulation, with roughly 150 cases described worldwide. Clinical presentation was heterogeneous, including two patients diagnosed at ages 47 and 72 with predominantly gastrointestinal and neurological phenotypes, and two previously undescribed genetic variants were reported. Nuclear magnetic resonance lipidomic and metabolomic analysis found HDL depletion in all patients alongside an increased abundance of VLDL with higher total lipid and cholesterol, and elevated triglyceride-rich intermediate-density lipoprotein, pointing to impaired clearance of triglyceride-rich lipoproteins and hepatic lipase activity. On top of this, a CETP-mediated increase in LDL-triglycerides produced a higher abundance of large LDL subtypes and less small dense LDL. The authors identify impaired triglyceride-rich lipoprotein clearance, hepatic lipase activity and CETP-mediated LDL remodelling as a pathophysiological hallmark of the disease.
Original abstract
Context: Tangier disease (TD) is a rare, autosomal recessive genetic disorder associated with a deficiency in cellular cholesterol export leading to cholesterol accumulation in peripheral tissues. With approximately 150 described cases, the disease is significantly understudied, and the clinical presentation appears to be heterogenous.
Objective: To investigate the phenotype and lipid metabolism in TD.
Design: Multicenter cohort study.
Patients: Four patients with TD.
Main Outcome Measures: Nuclear magnetic resonance (NMR)-based lipidomic and metabolomic analyses were performed in patients with TD and healthy controls.
Results: While showing similar laboratory patterns with respect to high-density lipoprotein (HDL) depletion, the clinical presentation of 4 TD patients was heterogenous with 2 patients diagnosed at 47 and 72 years having predominantly gastrointestinal and neurological phenotypes. Two previously undescribed variants (c.2418G > A, c.5055.del) were reported.Apart from pathognomonic changes in HDL composition, NMR spectroscopy revealed an increased abundance of very low-density lipoprotein (VLDL) with higher total lipid and cholesterol concentrations, pointing toward an impaired clearance of triglyceride-rich lipoproteins. Increased triglyceride-rich intermediate-density lipoprotein supports impaired hepatic lipase activity, together with a cholesteryl ester transfer protein-mediated increase in low-density lipoprotein (LDL)-triglycerides at higher abundance of large LDL subtypes and decreased small dense LDL.The lipid composition of HDL particles and LDL-1/LDL-4 remained the strongest differentiating factors as compared to healthy controls.
Conclusion: Clinical phenotypes of TD can be heterogeneous including gastrointestinal and neurological manifestations. Impaired triglyceride-rich lipoprotein clearance and hepatic lipase activity could be a pathophysiological hallmark of TD.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.