Human Apoa-II Inhibits the Hydrolysis of HDL... : Journal of Clinical Investigation (original) (raw)

Human Apoa-II Inhibits the Hydrolysis of HDL Triglyceride and the Decrease of HDL Size Induced by Hypertriglyceridemia and Cholesteryl Ester Transfer Protein in Transgenic Mice

Shaobin Zhong
Ira J. Goldberg
Can Bruce
Edward Rubin
Jan L. Breslow
Alan. Tall

Journal of Clinical Investigation

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2457

2467

December 1994

The plasma cholesteryl ester transfer protein (CETP) mediates the exchange of HDL cholesteryl esters with triglycerides of other lipoproteins.Subsequent lipolysis of the triglyceride-enriched HDL by hepatic lipase leads to reductions of HDL size and apoA-I content. To investigate a possible modulation of the effects of CETP by apoA-II, human CETP transgenic mice were cross-bred with transgenic mice expressing human apoA-II and, in some cases, human apoA-I and apoC-III (with human-like HDL and hypertriglyceridemia). CETP expression resulted in reductions of HDL and increases in VLDL cholesteryl ester in mice expressing human apoA-II, alone or in combination with apoA-I and apoC-III, indicating that apoA-II does not inhibit the cholesteryl ester transfer activity of CETP. However, CETP expression resulted in more prominent increases in HDL triglyceride in mice expressing both apoA-II and CETP, especially in CETP/apoA-II/apoAI-CIII transgenic mice. CETP expression caused dramatic reductions in HDL size and apoA-I content in apoAI-CIII transgenic mice, but not in apoA-II/AI-CIII transgenic mice. HDL prepared from mice of various genotypes showed inhibition of emulsion-based hepatic lipase activity in proportion to the apoA-II/apoA-I ratio of HDL. The presence of human apoA-II also inhibited mouse plasma hepatic lipase activity on HDL triglyceride. Thus, apoA-II does not inhibit the lipid transfer activity of CETP in vivo. However, coexpression of apoA-II with CETP results in HDL particles that are more triglyceride enriched and resistant to reductions in size and apoA-I content, reflecting inhibition of hepatic lipase by apoA-II. The inhibition of HDL remodeling by apoA-II could explain the relatively constant levels of HDL containing both apoA-I and apoA-II in human populations. (J. Clin. Invest. 1994. 94:2457-2467.) Key words: transgenic mice. cholesteryl ester transfer protein. apolipoprotein A-II. high density lipoproteins. hepatic lipase