ANGPTL3 Decreases Very Low Density Lipoprotein Triglyceride Clearance by Inhibition of Lipoprotein Lipase

Abstract

KK/San is a mutant mouse strain established in our laboratory from KK obese mice. KK/San mice show low plasma lipid levels compared with wild-type KK mice despite showing signs of hyperglycemia and hyperinsulinemia. Recently, we identified a mutation in the gene encoding angiopoietin-like protein 3 (Angptl3) in KK/ San mice, and injection of adenoviruses encoding Angptl3 or recombinant ANGPTL3 protein to mutant KK/San mice raised plasma lipid levels. To elucidate the regulatory mechanism of ANGPTL3 on lipid metabolism, we focused on the metabolic pathways of triglyceride in the present study. Overexpression of Angptl3 in KK/San mice resulted in a marked increase of triglyceride-enriched very low density lipoprotein (VLDL). In vivo studies using Triton WR1339 revealed that there is no significant difference between mutant and wild-type KK mice in the hepatic VLDL triglyceride secretion rate. However, turnover studies using radiolabeled VLDL revealed that the clearance of 3 H-triglyceride-labeled VLDL was significantly enhanced in KK/San mice, whereas the clearance of 125 I-labeled VLDL was only slightly enhanced. In vitro analysis of recombinant protein revealed that ANGPTL3 directly inhibits LPL activity. These data strongly support the hypothesis that ANGPTL3 is a new class of lipid metabolism modulator, which regulates VLDL triglyceride levels through the inhibition of LPL activity.Hyperlipidemia is a major risk factor of coronary heart disease. Variations in human plasma lipid levels result from both genetic and environmental factors. Genetic factors account for more than 50% of the variation in plasma lipid levels in the human population (1-4). Naturally occurring mutations that affect lipid metabolism in mice have also been reported (5-7). In most cases, the mutated genes have not yet been identified, but elucidating the mutations could lead to the identification of the relevant genes.KK obese mice have a multigenic syndrome of moderate obesity and a diabetic phenotype that resembles human hereditary type 2 diabetes; they show signs of hyperinsulinemia, hyperglycemia, and hyperlipidemia (8 -10). We have found that KK mice in our laboratory (KK/San) have significantly low plasma lipid levels despite showing signs of hyperinsulinemia and hyperglycemia (11). Genetic analysis shows that the mutant phenotype of KK/San mice is inherited recessively as a Mendelian trait. We therefore named this locus hypl (for hypolipidemia). We observed the autosomal recessive hypl phenotype in the progeny of the KK/San strain and mapped the locus to the middle of chromosome 4. We identified a mutation in the gene encoding angiopoietin-like protein 3 (Angptl3) as the cause of the hypl trait (12). The mRNA of Angptl3 is predominantly localized in the liver. The expression of Angptl3 in KK/San mice was found to be 1/30 to 1/40 that of wild-type mice. Overexpression of Angptl3 using adenoviruses or by an intravenous injection of the recombinant protein in KK/San mice elicited a marked increase in circulating plasma total cholesterol...

Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis

“…Shimizugawa et al reported that VLDL secretion was normal in Angptl3 −/− mice (8). However, those studies were performed in fasted animals, when the effects of ANGPTL8 would be least apparent, whereas our studies were performed at the end of the dark cycle in food-replete animals.…”

“…Both ANGPTLs inhibit LPL (6)(7)(8). Overexpression of either protein inhibits LPL activity and causes hypertriglyceridemia, whereas loss-of-function mutations lead to very low TG levels (7,8).…”

The Direct Peroxisome Proliferator-activated Receptor Target Fasting-induced Adipose Factor (FIAF/PGAR/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment

“…The low plasma triglyceride levels are possibly due to elevated lipoprotein lipase activity, which was reported to be inhibited by ANGPTL3 in vitro, whereas the low plasma free fatty acid levels may be connected to the impaired stimulatory effect of ANGPTL3 on adipose tissue lipolysis (21,22). Similar to ANGPTL3, there is evidence that FIAF also may inhibit lipoprotein lipase activity and hereby influence plasma levels of triglycerides (18,23), thus connecting FIAF to lipid metabolism.…”

Atypical angiopoietin-like protein that regulates ANGPTL3

“…ANGPTL3 is expressed almost exclusively in the liver (5,6), and is only modestly regulated by food intake (12). Angptl3 −/− mice have increased LPL activity (8,13,14), and recombinant ANGPTL3 inhibits LPL in vitro (6,13,15,16), leading several investigators to propose that ANGPTL3 raises plasma TAG levels by inhibiting LPL activity (13,14). However, the concentrations of ANGPTL3 used in these studies were supraphysiological.…”