Mechanisms
Endotoxin suppresses CETP via adrenal corticosteroid release, raising HDL in transgenic mice (J Clin Invest 1995)
Original title: Decreased cholesteryl ester transfer protein (CETP) mRNA and protein and increased high density lipoprotein following lipopolysaccharide administration in human CETP transgenic mice
Since HDL is thought to reduce endotoxin (lipopolysaccharide, LPS) toxicity and LPS is known to affect enzymes of HDL metabolism, this study examined LPS effects on CETP in human CETP-transgenic mice. LPS administration produced a rapid, marked decrease in hepatic CETP mRNA and plasma CETP concentration, an effect mimicked by corticosteroid injection and abolished by adrenalectomy, indicating it is largely mediated by adrenal corticosteroid release. LPS also caused disproportionate reductions in plasma CETP activity relative to mass and directly inhibited CETP activity when added to plasma. Manipulating CETP transgene expression showed that decreased plasma CETP was accompanied by increased HDL cholesterol while increased plasma CETP produced decreased HDL cholesterol, suggesting the LPS-induced fall in CETP is an adaptive response that raises HDL to help modify the response to endotoxin.
Original abstract
The plasma cholesteryl ester transfer protein (CETP) mediates the exchange of HDL cholesteryl esters (CE) and VLDL triglycerides leading to catabolism of HDL. There is some evidence that HDL ameliorates the toxicity of LPS, and LPS is known to influence several enzymes affecting HDL metabolism. Therefore, the effects of LPS on CETP and plasma lipoproteins were examined in human CETP transgenic mice. Administration of LPS to mice expressing a CETP transgene linked to its natural flanking sequences (NFR-CETP Tg) resulted in a rapid marked decrease in hepatic CETP mRNA and plasma CETP concentration. Corticosteroid injection produced a similar decrease in hepatic CETP mRNA and adrenalectomy abolished this response to LPS. LPS caused disproportionate reductions in plasma CETP activity compared to mass, and was found to be a potent inhibitor of CETP activity when added directly to plasma. LPS was injected into mice expressing (A) a human apoA-I transgene, (B) apoA-I and NFR-CETP transgenes, or (C) apoA-I and LPS-inducible metallothionein promoter-driven CETP transgenes, producing (A) minimal changes in HDL cholesterol, (B) decreased plasma CETP and increased HDL cholesterol, and (C) increased plasma CETP and decreased HDL cholesterol. Thus, LPS administration produces a profound decrease in hepatic CETP mRNA, primarily as a result of adrenal corticosteroid release. The decrease in plasma CETP activity after LPS administration may reflect both this effect as well as a direct interaction between CETP and LPS. The decrease of CETP in response to LPS has major effects on HDL levels, and may represent an adaptive response to preserve or increase HDL and thereby modify the response to LPS.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.