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

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