REMODELING OF THE HDL IN NIDDM - A FUNDAMENTAL ROLE FOR CHOLESTERYL ESTER TRANSFER PROTEIN

When the Ar gene is expressed in KK mice, the yellow offspring (KKA(y) mice) become obese, insulin resistant, hyperglycemic, and severely hy pertriglyceridemic, yet they maintain extraordinarily high plasma high -density lipoprotein (HDL) levels. Mice lack the ability to redistribu te neutral lipids among circulating lipoproteins, a process catalyzed in humans by cholesteryl ester transfer protein (CETP). To test the hy pothesis that it is the absence of CETP that allows these hypertriglyc eridemic mice to maintain high plasma HDL levels, simian CETP was expr essed in the KKA(y) mouse. The KKA(y)-CETP mice retained the principal characteristics of KKA(y) mice except that their plasma HDL levels we re reduced (from 159 +/- 25 to 25 +/- 6 mg/dl) and their free apolipop rotein 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 remodel ing of the HDL is responsible for the low levels of that lipoprotein t hat accompany hypertriglyceridemic non-insulin-dependent diabetes mell itus.