title: Fat paradox of steatohepatitis.
abstract: Alcoholic and non-alcoholic steatohepatitis (ASH and NASH) constitute two major types of chronic liver disease with worldwide prevalence and are histologically indistinguishable with shared pathogenetic mechanisms. More importantly, they have synergistic interactions for liver pathology. Comparative studies on ASH and NASH have been hampered by the use of different animal models with confounding variables, particularly those with extreme genetic, toxic, and malnutrition etiologies. The mouse intragastric model circumvents these problems and reproduces the natural course and etiological background of ASH and NASH. Further, our recent work reproduces a profound synergism between the two in the model. Intracellular accumulation of neural lipids is a hallmark biochemical feature of ASH and NASH. Although impaired lipid oxidation and export may contribute to this pathological change, enhanced lipogenic regulation is frequently encountered, as characterized by induction of lipogenic or adipogenic transcription factors (peroxisome proliferator-activated receptor [PPAR gamma], liver X receptor alpha[LXR alpha], sterol-regulatory element-binding protein-1c [SREBP-1c]). In contrast, we have recently defined transdifferentiation of hepatic stellate cells (HSC), a pivotal event in liver fibrogenesis, as an 'antilipogenic' or 'anti-adipogenic' phenomenon. Thus, there is an apparent paradox between hepatocytes and HSC in steatohepatitis in terms of the outcome of lipogenic regulation. Our recent work suggests that defective insulin signaling in activated HSC may be responsible for this paradox. Further, activated Wnt signaling is implicated in 'anti-adipogenic' stellate cell transdifferentiation in liver fibrogenesis.
authors.affiliation: USC-UCLA Research Center of ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. htsukamo@usc.edu
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Hongyun
authors.initials: H
authors.lastname: She
authors.forename: Saswati
authors.initials: S
authors.lastname: Hazra
authors.forename: Jason
authors.initials: J
authors.lastname: Cheng
authors.forename: Jiaohong
authors.initials: J
authors.lastname: Wang
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D005234:Fatty Liver / Q000209:etiology*; D005235:Fatty Liver, Alcoholic / Q000209:etiology; D006505:Hepatitis / Q000209:etiology*; D022781:Hepatocytes / Q000166:cytology; D006801:Humans