Over 10 million patients undergoing non-cardiac surgery each year face major cardiovascular complications within 30 days, many due to destabilized atherosclerotic plaques. Reverse cholesterol transpor Show more
Over 10 million patients undergoing non-cardiac surgery each year face major cardiovascular complications within 30 days, many due to destabilized atherosclerotic plaques. Reverse cholesterol transport (RCT), driven by HDL and Apoa1, protects against plaque progression, but the effects of surgical inflammation on this pathway remain unclear. Using an abdominal laparotomy model in ApoE Show less
LIPC encodes hepatic lipase (HL), a liver-bound protein with both phospholipase and triglyceride lipase activity, and involved in the catabolism of circulating lipoproteins. We recently identified the Show more
LIPC encodes hepatic lipase (HL), a liver-bound protein with both phospholipase and triglyceride lipase activity, and involved in the catabolism of circulating lipoproteins. We recently identified the gain-of-function variant HL-E97G, with selectively increased phospholipase activity, as a new genetic cause of familial combined hypocholesterolaemia in humans. The role of HL in the development of atherosclerosis remains controversial. In this context, the action of HL-E97G on the development of atherosclerosis remains unknown. To evaluate the lipid-lowering and anti-atherogenic properties of HL-E97G vs. wildtype HL (HL-WT) in hypercholesterolaemic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, and to assess dependence of these effects on the LDL receptor (LDLR) pathway in LDLR-deficient (Ldlr-/-) mice. APOE*3.Leiden.CETP mice or Ldlr-/- mice received an intravenous injection of AAV8 expressing either eGFP (control), HL-WT or HL-E97G (3 × 1011 GC/mouse) while being fed pro-atherogenic diets. Plasma cholesterol levels were measured monthly, and aortic atherosclerotic lesion sizes were assessed at termination. HL-E97G largely decreased plasma total cholesterol exposure in APOE*3-Leiden.CETP mice (-63% vs. control; -58% vs. HL-WT), resulting at least in part from increased uptake of (V)LDL by the liver, accompanied by a marked decrease in atherosclerotic lesion size (-98% vs. control; -97% vs. HL-WT) in the aortic root. Importantly, HL-E97G also strongly reduced plasma cholesterol exposure in Ldlr-/- mice (-80% vs. control; -77% vs. HL-WT), and decreased atherosclerotic lesion size in the aortic root (-54% vs. control; -41% vs. HL-WT) and the aortic arch (-73% vs. control; -70% vs. HL-WT). HL-E97G strongly reduces plasma cholesterol levels, by increasing the uptake of (V)LDL, to decrease atherosclerosis development in mice independently of the LDLR pathway. These data suggest that modulating HL function is a promising tool in patients with familial hypercholesterolaemia. Show less