title: Activation of Insulin-PI3K/Akt-p70S6K Pathway in Hepatic Stellate Cells Contributes to Fibrosis in Nonalcoholic Steatohepatitis.
abstract: Hyperinsulinemia and insulin resistance are hallmark features of nonalcoholic fatty liver disease and steatohepatitis (NASH). It remains unclear whether and how insulin contributes to the development of fibrosis in NASH. In this study, we explored insulin signaling in the regulation of hepatic stellate cell (HSC) activation and the progression of NASH-fibrosis.
  
  
  
  Phosphorylation of Akt and p70S6K were examined in primary HSC and in a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet for 24 weeks. HSC activation was analyzed for the changes in cell morphology, intracellular lipid droplets, expression of α-SMA and cell proliferation. The serum markers and histology for NASH-fibrosis were also characterized in animals.
  
  
  
  Insulin enhanced the expression of smooth muscle actin-α in quiescent but not in activated HSC in culture. Insulin-mediated activation of the PI3K/Akt-p70S6K pathway was involved in the regulation of profibrogenic effects of insulin. Although insulin did not stimulate HSC proliferation directly, the insulin-PI3K/Akt-p70S6K pathway was necessary for serum-enhanced cell proliferation during initial HSC activation. In a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet, hyperinsulinemia is associated with the activation of p70S6K and enhanced fibrosis.
  
  
  
  The insulin-PI3K/Akt-p70S6K pathway plays an important role in the early activation of HSC. The profibrogenic effect of insulin is dependent on the activation stage of HSC. Dysregulation of the insulin pathway likely correlates with the development of fibrosis in NASH, suggesting a potentially novel antifibrotic target of inhibiting insulin signaling in HSC.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, VA Loma Linda Healthcare System, Loma Linda University, 11201 Benton Street, Loma Linda, CA, 92357, USA. cindy.cai3@va.gov.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University Liver Center, Saint Louis University School of Medicine, 3635 Vista Avenue at Grand Blvd, St. Louis, MO, 63110, USA. cindy.cai3@va.gov.
authors.forename: Cindy X
authors.identifier: 0000-0002-2673-8578
authors.initials: CX
authors.lastname: Cai
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, VA Loma Linda Healthcare System, Loma Linda University, 11201 Benton Street, Loma Linda, CA, 92357, USA.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University Liver Center, Saint Louis University School of Medicine, 3635 Vista Avenue at Grand Blvd, St. Louis, MO, 63110, USA.
authors.forename: Hema
authors.initials: H
authors.lastname: Buddha
authors.affiliation: Department of Pathology, VA Loma Linda Healthcare System, Loma Linda University, 11201 Benton Street, Loma Linda, CA, 92357, USA.
authors.forename: Shobha
authors.initials: S
authors.lastname: Castelino-Prabhu
authors.affiliation: Division of Nephrology, Department of Medicine, VA Loma Linda Healthcare System, Loma Linda University, 11201 Benton Street, Loma Linda, CA, 92357, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University Liver Center, Saint Louis University School of Medicine, 3635 Vista Avenue at Grand Blvd, St. Louis, MO, 63110, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Britton
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University Liver Center, Saint Louis University School of Medicine, 3635 Vista Avenue at Grand Blvd, St. Louis, MO, 63110, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Bacon
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University Liver Center, Saint Louis University School of Medicine, 3635 Vista Avenue at Grand Blvd, St. Louis, MO, 63110, USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Neuschwander-Tetri
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology / Q000633:toxicity; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa
keywords: Hepatic stellate cells; High-fat and high-cholesterol diet; Insulin signaling pathway; Liver fibrosis; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis