Abstract
Nonalcoholic steatohepatitis (NASH) comprises dysregulation of lipid metabolism and inflammation. Identification of the various genetic and environmental susceptibility factors for NASH may provide novel treatments to limit inflammation and fibrosis in patients. This study utilized a mouse model of hypercholesterolemia, low-density lipoprotein receptor knockout (LDLr-/-) mice fed a high-fat diet for 5 months, to test the hypothesis that farnesoid X receptor (FXR) deficiency contributed to NASH development. Either the high-fat diet or FXR deficiency increased serum alanine aminotransferase activity, whereas only FXR deficiency increased bile acid and alkaline phosphatase levels. FXR deficiency and high-fat feeding increased serum cholesterol and triglycerides. Although high fat led to macrosteatosis and hepatocyte ballooning in livers of mice regardless of genotype, no inflammatory infiltrate was observed in the livers of LDLr-/- mice. In contrast, in the livers of LDLr-/-/FXR-/- mice, foci of inflammatory cells were observed occasionally when fed the control diet and were greatly increased when fed the high-fat diet. Consistent with enhanced inflammatory cells, hepatic levels of tumor necrosis factor α and intercellular adhesion molecule-1 mRNA were increased by the high-fat diet in LDLr-/-/FXR-/- mice. In agreement with elevated levels of procollagen 1α1 and TGF-β mRNA, type 1 collagen protein levels were increased in livers of LDLr-/-/FXR-/- mice fed a high-fat diet. In conclusion, FXR deficiency induces pathologic manifestations required for NASH diagnosis in a mouse model of hypercholesterolemia, including macrosteatosis, hepatocyte ballooning, and inflammation, which suggest a combination of FXR deficiency and high-fat diet is a risk factor for NASH development, and activation of FXR may be a therapeutic intervention in the treatment of NASH.
Footnotes
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This work was supported by National Institutes of Health [Grant P20 RR021940]; and by the American Heart Association [Grants 08351216, P20 RR015563, K12 HD052027, R01 DK031343].
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B.K. and J.P.L. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.144600.
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ABBREVIATIONS: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; FXR, farnesoid X receptor; MCD, methionine-choline-deficient; LDL, low-density lipoprotein; LDLr, LDL receptor; ALT, alanine aminotransferase; ALP, alkaline phosphatase; PCR, polymerase chain reaction; Q-PCR, quantitative PCR; TNF, tumor necrosis factor; ICAM, intercellular adhesion molecule; SMA, smooth muscle actin; TIMP, tissue inhibitor of metalloproteinase; TGF, transforming growth factor.
- Received August 7, 2008.
- Accepted October 22, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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