title: Ursodeoxycholic acid improves insulin sensitivity and hepatic steatosis by inducing the excretion of hepatic lipids in high-fat diet-fed KK-Ay mice.
abstract: Type 2 diabetes mellitus is frequently accompanied by fatty liver/nonalcoholic fatty liver disease. Hence, accumulation of lipids in the liver is considered to be one of the risk factors for insulin resistance and metabolic syndrome. Ursodeoxycholic acid (UDCA) is widely used for the treatment of liver dysfunction. We investigated the therapeutic effects of UDCA on type 2 diabetes mellitus exacerbating hepatic steatosis and the underlying mechanisms of its action using KK-A(y) mice fed a high-fat diet. KK-A(y) mice were prefed a high-fat diet; and 50, 150, and 450 mg/kg of UDCA was orally administered for 2 or 3 weeks. Administration of UDCA decreased fasting hyperglycemia and hyperinsulinemia. Hyperinsulinemic-euglycemic clamp analyses showed that UDCA improved hepatic (but not peripheral) insulin resistance. Hepatic triglyceride and cholesterol contents were significantly reduced by treatment with UDCA, although the genes involved in the synthesis of fatty acids and cholesterol, including fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, were upregulated. Fecal levels of bile acids, neutral sterols, fatty acids, and phospholipids were significantly increased by UDCA treatment. The gene expression levels and protein phosphorylation levels of endoplasmic reticulum stress markers were not changed by UDCA treatment. These results indicate that UDCA ameliorates hyperglycemia and hyperinsulinemia by improving hepatic insulin resistance and steatosis in high-fat diet-fed KK-A(y) mice. Reduction of hepatic lipids might be due to their excretion in feces, followed by enhanced utilization of glucose for the synthesis of fatty acids and cholesterol. Ursodeoxycholic acid should be effective for the treatment of type 2 diabetes mellitus accompanying hepatic steatosis.
authors.affiliation: Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama 335-8505, Japan. tsuchida.takuma@mx.mt-pharma.co.jp
authors.forename: Takuma
authors.initials: T
authors.lastname: Tsuchida
authors.forename: Muneshige
authors.initials: M
authors.lastname: Shiraishi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohta
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sakai
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ishii
mesh_terms: D000818:Animals; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D002784:Cholesterol / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D059305:Diet, High-Fat / Q000009:adverse effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005227:Fatty Acids / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism; D020869:Gene Expression Profiling; D006943:Hyperglycemia / Q000188:drug therapy; D006946:Hyperinsulinism / Q000188:drug therapy; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D015854:Up-Regulation; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
chemical_list: D002756:Cholagogues and Choleretics; D005227:Fatty Acids; D014580:Ursodeoxycholic Acid; D002784:Cholesterol