Cis- and Trans-Palmitoleic Acid Isomers Regulate Cholesterol Metabolism in Different Ways

Abstract

Hypercholesterolemia is a preventable risk factor for atherosclerosis and cardiovascular disease. However, the mechanisms wherebycis-palmitoleic acid (cPOA) andtrans-palmitoleic acid (tPOA) promote cholesterol homeostasis and ameliorate hypercholesterolemia remain elusive. To investigate the effects ofcPOA andtPOA on cholesterol metabolism and its mechanisms, we induced hypercholesterolemia in mice using a high-fat diet and then intragastrically administeredcPOA ortPOA once daily for 4 weeks.tPOA administration reduced serum cholesterol, low-density lipoprotein, high-density lipoprotein, and hepatic free cholesterol and total bile acids (TBAs). Conversely,cPOA had no effect on these parameters except for TBAs. Histological examination of the liver, however, revealed thatcPOA ameliorated hepatic steatosis more effectively thantPOA.tPOA significantly reduced the expression of 3-hydroxy-3-methyl glutaryl coenzyme reductase (HMGCR), LXRα, and intestinal Niemann-Pick C1-Like 1 (NPC1L1) and increased cholesterol 7-alpha hydroxylase (CYP7A1) in the liver, whereascPOA reduced the expression of HMGCR and CYP7A1 in the liver and had no effect on intestinal NPC1L1. In summary, our results suggest thatcPOA andtPOA reduce cholesterol synthesis by decreasing HMGCR levels. Furthermore,tPOA, but notcPOA, inhibited intestinal cholesterol absorption by downregulating NPC1L1. Both high-dosetPOA andcPOA may promote the conversion of cholesterol into bile acids by upregulating CYP7A1.tPOA andcPOA prevent hypercholesterolemia via distinct mechanisms.