Angptl4 deficiency decreases serum triglyceride levels in low-density lipoprotein receptor knockout mice and streptozotocin-induced diabetic mice

Angiopoietin-like protein family 4 (Angptl4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). In familial hypercholesterolemia (FH), individuals lacking low-density lipoprotein receptor (LDLR) present not only hypercholesterolemia, but also increased plasma triglyceride (TG)-rich lipoprotein remnants, and develop atherosclerosis. In addition, the most common type of dyslipidemia in individuals with diabetes is increased TG levels.We first generated LDLR−/−Angptl4−/− mice to study the effect of Angptl4 deficiency on the lipid metabolism. Fasting total cholesterol, VLDL-C, LDL-C, HDL-C and TG levels were decreased in LDLR−/−Angptl4−/− mice compared with LDLR−/−Angptl4+/+ mice. In particular, post olive oil-loaded TG excursion were largely attenuated in LDLR−/−Angptl4−/− mice compared with LDLR−/−Angptl4+/+ mice. We next introduced diabetes by streptozotocin (STZ) treatment in Angptl4−/− mice and examined the impacts of Angptl4 deficiency. Compared with diabetic Angptl4+/+ mice, diabetic Angptl4−/− mice showed the improvement of fasting and postprandial hypertriglyceridemia as well. Thus, targeted silencing of Angptl4 offers a potential therapeutic strategy for the treatment of dyslipidemia in individuals with FH and insulin deficient diabetes.

► Angptl4 is known as an inhibitor of lipoprotein lipase action.
► We have shown that serum lipid profiles are decreased in LDLR−/−Angptl4−/−mice.
► Postprandial hypertriglyceridemia was remarkably improved in LDLR−/−Angptl4−/− mice upon olive-oil loading.
► Angptl4 deficiency improved fasting and postprandial hypertriglyceridemia instreptozotocin-treated mice as well.
► The silencing of Angptl4 could offer a therapeutic strategy for the treatment of FH and dyslipidemia of diabetes mellitus.