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

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