Gastroenterology
Volume 142, Issue 1 , Pages 152-164.e10 , January 2012

A High-Cholesterol Diet Exacerbates Liver Fibrosis in Mice via Accumulation of Free Cholesterol in Hepatic Stellate Cells

  • Toshiaki Teratani

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  • ,
  • Kengo Tomita

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, Saitama, Japan
    • Corresponding Author InformationReprint requests Address requests for reprints to: Kengo Tomita, MD, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan. fax: (81) 4-2996-5201
  • ,
  • Takahiro Suzuki

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  • ,
  • Tetsuya Oshikawa

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  • ,
  • Hirokazu Yokoyama

      Affiliations

    • Health Center, Keio University School of Medicine, Tokyo, Japan
  • ,
  • Katsuyoshi Shimamura

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  • ,
  • Susumu Tominaga

      Affiliations

    • Department of Pathology and Laboratory Medicine, National Defense Medical College, Saitama, Japan
  • ,
  • Sadayuki Hiroi

      Affiliations

    • Department of Pathology and Laboratory Medicine, National Defense Medical College, Saitama, Japan
  • ,
  • Rie Irie

      Affiliations

    • Department of Pathology, Kawasaki Municipal Hospital, Kanagawa, Japan
  • ,
  • Yoshikiyo Okada

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, Saitama, Japan
  • ,
  • Chie Kurihara

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, Saitama, Japan
  • ,
  • Hirotoshi Ebinuma

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  • ,
  • Hidetsugu Saito

      Affiliations

    • Graduate School of Pharmaceutical Sciences, Keio University Faculty of Pharmacy, Tokyo, Japan
  • ,
  • Ryota Hokari

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, Saitama, Japan
  • ,
  • Kazuo Sugiyama

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  • ,
  • Takanori Kanai

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  • ,
  • Soichiro Miura

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, Saitama, Japan
  • ,
  • Toshifumi Hibi

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

Received 13 November 2010 ,Accepted 24 September 2011.

References 

  1. Friedman SL . Mechanisms of hepatic fibrogenesis . Gastroenterology . 2008;134:1655–1669
  2. Ioannou GN , Morrow OB , Connole ML , et al.  Association between dietary nutrient composition and the incidence of cirrhosis or liver cancer in the United States population . Hepatology . 2009;50:175–184
  3. Ekstedt M , Franzén LE , Mathiesen UL , et al.  Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study . J Hepatol . 2007;47:135–141
  4. Yoneda M , Fujita K , Nozaki Y , et al.  Efficacy of ezetimibe for the treatment of non-alcoholic steatohepatitis: an open-label, pilot study . Hepatol Res . 2010;40:613–621
  5. Sumiyoshi M , Sakanaka M , Kimura Y . Chronic intake of a high-cholesterol diet resulted in hepatic steatosis, focal nodular hyperplasia and fibrosis in non-obese mice . Br J Nutr . 2010;103:378–385
  6. Kainuma M , Fujimoto M , Sekiya N , et al.  Cholesterol-fed rabbit as a unique model of nonalcoholic, nonobese, non-insulin-resistant fatty liver disease with characteristic fibrosis . J Gastroenterol . 2006;41:971–980
  7. Vergnes L , Phan J , Strauss M , et al.  Cholesterol and cholate components of an atherogenic diet induce distinct stages of hepatic inflammatory gene expression . J Biol Chem . 2003;278:42774–42784
  8. Malhi H , Bronk SF , Werneburg NW , et al.  Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis . J Biol Chem . 2006;281:12093–12101
  9. Jin LW , Shie FS , Maezawa I , et al.  Intracellular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities . Am J Pathol . 2004;164:975–985
  10. Liao G , Yao Y , Liu J , et al.  Cholesterol accumulation is associated with lysosomal dysfunction and autophagic stress in Npc1 −/− mouse brain . Am J Pathol . 2007;171:962–975
  11. Li Y , Schwabe RF , DeVries-Seimon T , et al.  Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis . J Biol Chem . 2005;280:21763–21772
  12. Seki E , De Minicis S , Osterreicher CH , et al.  TLR4 enhances TGF-beta signaling and hepatic fibrosis . Nat Med . 2007;13:1324–1332
  13. Paik YH , Schwabe RF , Bataller R , et al.  Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells . Hepatology . 2003;37:1043–1055
  14. Wang Y , Chen T , Han C , et al.  Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4 . Blood . 2007;110:962–971
  15. Suzuki M , Sugimoto Y , Ohsaki Y , et al.  Endosomal accumulation of Toll-like receptor 4 causes constitutive secretion of cytokines and activation of signal transducers and activators of transcription in Niemann-Pick disease type C (NPC) fibroblasts: a potential basis for glial cell activation in the NPC brain . J Neurosci . 2007;27:1879–1891
  16. Chen H , Yang J , Low PS , et al.  Cholesterol level regulates endosome motility via Rab proteins . Biophys J . 2008;94:1508–1520
  17. Marí M , Caballero F , Colell A , et al.  Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis . Cell Metab . 2006;4:185–198
  18. Bohan A , Chen WS , Denson LA , et al.  Tumor necrosis factor alpha-dependent up-regulation of Lrh-1 and Mrp3(Abcc3) reduces liver injury in obstructive cholestasis . J Biol Chem . 2003;278:36688–36698
  19. Simeonova PP , Gallucci RM , Hulderman T , et al.  The role of tumor necrosis factor-alpha in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride . Toxicol Appl Pharmacol . 2001;177:112–120
  20. Wouters K , van Gorp PJ , Bieghs V , et al.  Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis . Hepatology . 2008;48:474–486

 Conflicts of interest The authors disclose no conflicts.

 Funding This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to K. Tomita).

PII: S0016-5085(11)01375-8

doi: 10.1053/j.gastro.2011.09.049

Gastroenterology
Volume 142, Issue 1 , Pages 152-164.e10 , January 2012