Involvement of microsomal triglyceride transfer protein in nonalcoholic steatohepatitis in novel spontaneous mouse model

• Published in: Journal of hepatology Vol. 52; no. 6; pp. 903 - 912
• Main Authors: Shindo, Nobuyasu, Fujisawa, Tomomi, Sugimoto, Ken, Nojima, Koji, Oze-Fukai, Aya, Yoshikawa, Yuki, Wang, Xiang, Yasuda, Osamu, Ikegami, Hiroshi, Rakugi, Hiromi
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.06.2010; Elsevier
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cholesterol, VLDL - blood; Diabetes. Impaired glucose tolerance; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty Liver - metabolism; Fatty Liver - pathology; Fatty Liver - physiopathology; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression - physiology; Glucose intolerance; Glucose Intolerance - metabolism; Glucose Intolerance - pathology; Glucose Intolerance - physiopathology; Insulin - blood; Insulin resistance; Insulin Resistance - physiology; Lipid Metabolism - genetics; Liver - metabolism; Liver - pathology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver Cirrhosis - physiopathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microsomal triglyceride transfer protein; Microsomes, Liver - metabolism; Microsomes, Liver - pathology; Nonalcoholic steatohepatitis; Phenotype; Spontaneous model; Transfection; Triglycerides - metabolism; triglyceride; NAFLD; MCP-1; Spontaneous model; Glucose intolerance; Irs1; MTP; alanine aminotransferase; monocyte chemoattractant protein-1; microsomal triglyceride transfer protein; ALT; Irs2; F4/80; nonalcoholic steatohepatitis; B6 mouse; FLS mouse; Fatty Liver Shionogi mouse; VLDL; gamma-glutamyltransferase; ApoB; HPLC; cell surface glycoprotein F4/80; BMI; AST; body mass index; homeostasis model assessment ratio; NASH; aspartate aminotransferase; C57BL/6 mouse; intraperitoneal glucose tolerance test; nonalcoholic fatty liver disease; high performance liquid chromatography; insulin receptor substrate 2; TG; insulin receptor substrate 1; TNF-α; GGT; tumor necrosis factor-α; Insulin resistance; very low density lipoprotein; HOMA-R; ipGTT; apolipoprotein B; Nonalcoholic steatohepatitis; Microsomal triglyceride transfer protein; Endocrinopathy; Spontaneous; Rodentia; Metabolic diseases; Triglyceride; Protein; Target tissue resistance; Vertebrata; Mammalia; Mouse; Animal; Gastroenterology; Models; Impaired glucose tolerance
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2009.12.033

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is currently recognized as a global health issue and encompasses a wide spectrum of entities, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). The lack of a spontaneous animal model of NASH, however, has hampered basic research in this field. Methods We examined the hepatic lesions in the inbred Fatty Liver Shionogi (FLS) mouse, which exhibits type 2 diabetes, and investigated the molecular mechanism leading to NAFLD/NASH. Using vector-mediated hepatic expression of microsomal triglyceride transfer protein (MTP), a key molecule for very low density lipoprotein (VLDL) assembly and export, its contribution to the hepatic lesions as well as to glucose intolerance was examined. Results The FLS mouse, maintained on normal chow, exhibited excessive hepatic triglyceride (TG) accumulation due to impaired VLDL secretion, and subsequently hepatic lesions comparable to NASH, with increased expression of inflammatory molecules as well as insulin resistance. Gene expression and Western blot analyses demonstrated reduced hepatic expression of MTP in the FLS mouse. Hepatic induction of MTP resulted in a reduction in hepatic TG accumulation, improvement of VLDL export, and amelioration of NASH-like lesions, as well as glucose intolerance. Conclusions These data suggest that the FLS mouse could serve as a spontaneous model of NASH with insulin resistance, and that reduced MTP is involved in the development of NASH, pointing towards MTP as a critical target for the prevention and treatment of NASH.