HDL biology
Expressing simian CETP in obese diabetic KKAy mice cuts HDL from 159 to 25 mg/dl by enriching HDL with triglyceride 10-fold (Am J Physiol 1998)
Original title: Remodeling of the HDL in NIDDM: a fundamental role for cholesteryl ester transfer protein
The Ay gene expressed in KK mice produces obese, insulin-resistant, hyperglycemic, and severely hypertriglyceridemic KKAy mice that nonetheless maintain extraordinarily high plasma HDL, since mice naturally lack CETP and cannot redistribute neutral lipids among lipoproteins. To test whether this CETP deficiency explains the high HDL, the authors expressed simian CETP in KKAy mice. The resulting KKAy-CETP mice retained the principal features of KKAy mice, but plasma HDL fell from 159 +/- 25 to 25 +/- 6 mg/dl while free apolipoprotein A-I rose from 7 +/- 3 to 22 +/- 6 mg/dl. These changes appeared to result from CETP-induced enrichment of HDL with triglyceride (from 6 +/- 2 to 60 +/- 18 mol triglyceride per mol HDL), rendering HDL susceptible to destruction by lipases. This supports CETP-mediated HDL remodeling as the cause of low HDL in hypertriglyceridemic NIDDM.
Original abstract
When the Ay gene is expressed in KK mice, the yellow offspring (KKAy mice) become obese, insulin resistant, hyperglycemic, and severely hypertriglyceridemic, yet they maintain extraordinarily high plasma high-density lipoprotein (HDL) levels. Mice lack the ability to redistribute neutral lipids among circulating lipoproteins, a process catalyzed in humans by cholesteryl ester transfer protein (CETP). To test the hypothesis that it is the absence of CETP that allows these hypertriglyceridemic mice to maintain high plasma HDL levels, simian CETP was expressed in the KKAy mouse. The KKAy-CETP mice retained the principal characteristics of KKAy mice except that their plasma HDL levels were reduced (from 159 +/- 25 to 25 +/- 6 mg/dl) and their free apolipoprotein A-I concentrations increased (from 7 +/- 3 to 22 +/- 6 mg/dl). These changes appeared to result from a CETP-induced enrichment of the HDL with triglyceride (from 6 +/- 2 to 60 +/- 18 mol of triglyceride/mol of HDL), an alteration that renders HDL susceptible to destruction by lipases. These data support the premise that CETP-mediated remodeling of the HDL is responsible for the low levels of that lipoprotein that accompany hypertriglyceridemic non-insulin-dependent diabetes mellitus.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.