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 whereby <i>cis</i>-palmitoleic acid (<i>c</i>POA) and <i>trans</i>-palmitoleic acid (<i>t</i>POA) promote cholesterol homeostasis and ameliorate hypercholesterolemia remain elusive. To investigate the effects of <i>c</i>POA and <i>t</i>POA on cholesterol metabolism and its mechanisms, we induced hypercholesterolemia in mice using a high-fat diet and then intragastrically administered <i>c</i>POA or <i>t</i>POA once daily for 4 weeks. <i>t</i>POA administration reduced serum cholesterol, low-density lipoprotein, high-density lipoprotein, and hepatic free cholesterol and total bile acids (TBAs). Conversely, <i>c</i>POA had no effect on these parameters except for TBAs. Histological examination of the liver, however, revealed that <i>c</i>POA ameliorated hepatic steatosis more effectively than <i>t</i>POA. <i>t</i>POA 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, whereas <i>c</i>POA reduced the expression of HMGCR and CYP7A1 in the liver and had no effect on intestinal NPC1L1. In summary, our results suggest that <i>c</i>POA and <i>t</i>POA reduce cholesterol synthesis by decreasing HMGCR levels. Furthermore, <i>t</i>POA, but not <i>c</i>POA, inhibited intestinal cholesterol absorption by downregulating NPC1L1. Both high-dose <i>t</i>POA and <i>c</i>POA may promote the conversion of cholesterol into bile acids by upregulating CYP7A1. <i>t</i>POA and <i>c</i>POA prevent hypercholesterolemia via distinct mechanisms.