UCLA

Apolipoprotein AV (APOA5), a low-abundance apolipoprotein, has large effects on plasma triglyceride (TG) levels. APOA5 deficiency causes hypertriglyceridemia in humans and in mice, whereas mice expressing a human APOA5 transgene have low plasma TG levels. The lipolytic processing of TG-rich lipoproteins (TRLs) is impaired by a deficiency of APOA5, but for years the underlying cause remained unclear. This dissertation reviews my work on the mechanisms by which APOA5 regulates plasma TG metabolism. Lipoprotein lipase (LPL), the principal intravascular TG hydrolase, is responsible for TRL processing. In Chapter 2, with multiple approaches, I showed that Apoa5 deficiency reduces amounts of intracapillary LPL thereby causing hypertriglyceridemia. In Chapter 3, I showed that the reduced amounts of intracapillary LPL in Apoa5–/– mice results from unrestrained activity of the angiopoietin-like protein 3/8 complex (ANGPTL3/8). I was inspired by a biochemical finding—that APOA5 binds to ANGPTL3/8 and suppresses its ability to inhibit LPL activity. I suspected that ANGPTL3/8 also functions to detach LPL from its binding sites. Indeed, ANGPTL3/8 detaches LPL from the surface of cultured cells, and the ANGPTL3/8-mediated detachment could be blocked by an inhibitory ANGPTL3/8-specific monoclonal antibody (mAb) IBA490 and by APOA5. In Apoa5–/– mice, IBA490 had similar effects to APOA5; it increases intracapillary LPL levels and reduces plasma TG levels. In Chapter 4, I narrowed down APOA5 sequences that regulate plasma TG metabolism to its last 40 amino acids. Inspired by genetic studies, I suspected that carboxyl-terminal APOA5 sequences interact with ANGPTL3/8. I showed that mouse wild-type (WT) APOA5, but not a mutant mouse APOA5 lacking its last 40 residues (APOA5∆40), binds to ANGPTL3/8 and suppresses its activity. In Apoa5–/– mice, WT-APOA5, but not APOA5∆40, increases intracapillary LPL levels and lowers plasma TG levels. Finally, an inhibitory mAb IBA707 against the last 40 amino acids of mouse APOA5 reduces intracapillary LPL levels and causes hypertriglyceridemia in WT mice. After 25 years of confusion, my studies elucidated how APOA5 functions. APOA5 lowers plasma TG levels by binding to ANGPTL3/8 and suppressing its ability to inactivate LPL activity and detach LPL from its intravascular binding sites.