title: Lipid-lowering agents inhibit hepatic steatosis in a non-alcoholic steatohepatitis-derived hepatocellular carcinoma mouse model.
abstract: Non-alcoholic fatty liver disease (NAFLD) is associated with various metabolic disorders, and the therapeutic strategies for treating NAFLD and non-alcoholic steatohepatitis (NASH) have not been fully established. In the present study, we examined whether lipid-lowering agents inhibited the progression of NAFLD and tumorigenesis in a non-alcoholic steatohepatitis-derived hepatocellular carcinoma model mouse (STAM mice) generated by streptozotocin injection and a high-fat diet. Seven-week-old STAM mice were divided into groups fed a high-fat diet (Ctl) or a high-fat diet supplemented with ezetimibe (Ez), fenofibrate (Ff), rosuvastatin (Rs), ezetimibe plus fenofibrate (EF), or ezetimibe plus rosuvastatin (ER) for 4 weeks. At the end of the experiments, an oral glucose tolerance test, an insulin tolerance test, biochemical analyses using serum and liver, and a histological analysis of liver were performed in 11-week-old STAM mice. The lipid-lowering agents did not affect the body weight or the casual blood glucose levels in any of the groups. The serum triglyceride level was significantly decreased by Ff, Rs, and EF. Glucose tolerance was improved by Ez and Ff, but none of these agents improved insulin sensitivity. A histochemical analysis revealed that the lipid-lowering agents, with the exception of Rs, significantly inhibited the progression of hepatic steatosis. Nonetheless, no significant changes in the incidence of hepatic tumors were observed in any of the groups. Lipid-lowering agents inhibited the progression of hepatic steatosis without suppressing tumorigenesis in STAM mice. Our data has implications for the mechanism underlying steatosis-independent hepatic tumorigenesis in mice.
authors.affiliation: Department of Endocrinology and Metabolism, Yokohama-City University, Yokohama, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Orime
authors.affiliation: Department of Endocrinology and Metabolism, Yokohama-City University, Yokohama, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Shirakawa
authors.affiliation: Department of Endocrinology and Metabolism, Yokohama-City University, Yokohama, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Togashi
authors.affiliation: Department of Endocrinology and Metabolism, Yokohama-City University, Yokohama, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Tajima
authors.affiliation: Department of Endocrinology and Metabolism, Yokohama-City University, Yokohama, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Molecular Pathology, Yokohama-City University, Yokohama, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.affiliation: Department of Endocrinology and Metabolism, Yokohama-City University, Yokohama, Japan. Electronic address: terauchi-tky@umin.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000150:complications* / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000150:complications* / Q000473:pathology; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D000960:Hypolipidemic Agents; D014280:Triglycerides
keywords: Ezetimibe; Fibrate; Hepatocellular carcinoma; Nonalcoholic steatohepatitis; Statin