The Niemann-Pick C1 Like 1 (NPC1L1) Inhibitor Ezetimibe Improves Metabolic Disease Via Decreased Liver X Receptor (LXR) Activity in Liver of Obese Male Mice

• Published in: Endocrinology (Philadelphia) Vol. 155; no. 8; pp. 2810 - 2819
• Main Authors: Sugizaki, Taichi, Watanabe, Mitsuhiro, Horai, Yasushi, Kaneko-Iwasaki, Nao, Arita, Eri, Miyazaki, Teruo, Morimoto, Kohkichi, Honda, Akira, Irie, Junichiro, Itoh, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.08.2014
• Subjects: Agonists; Animals; Anticholesteremic Agents - pharmacology; Anticholesteremic Agents - therapeutic use; Azetidines - pharmacology; Azetidines - therapeutic use; c-Jun protein; Cardiovascular disease; Cardiovascular diseases; Cells, Cultured; Cholesterol; Coronary artery disease; Cytochrome P450; Cytochromes P450; Desaturase; Diabetes mellitus; Diet, High-Fat - adverse effects; Dyslipidemia; Esters; Ezetimibe; Fatty liver; Fatty Liver - drug therapy; Fatty Liver - etiology; Fatty Liver - metabolism; Glucose Metabolism Disorders - drug therapy; Glucose Metabolism Disorders - etiology; Heart diseases; Hepatocytes; Hepatocytes - metabolism; High fat diet; Homeostasis; Insulin; Insulin resistance; Intestines - drug effects; Intestines - metabolism; JNK protein; Kinases; Lipid Metabolism - drug effects; Lipids; Liver; Liver diseases; Liver X Receptors; Male; Males; Membrane Transport Proteins - metabolism; Metabolic disorders; Metabolic syndrome; Mice; Mice, Obese; NAD(P)H oxidase; Orphan Nuclear Receptors - antagonists & inhibitors; Orphan Nuclear Receptors - metabolism; Oxidation; Oxidative stress; Pathogenesis; Phosphorylation; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Receptors; Stearoyl-CoA Desaturase - antagonists & inhibitors; Stearoyl-CoA Desaturase - genetics; Transcription factors; Triglycerides
• ISSN: 0013-7227; 1945-7170; 1945-7170
• DOI: 10.1210/en.2013-2143

Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-Ay mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic β-oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome.