Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis

Authors

  • Kanji Yamaguchi,

    1. Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
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  • Liu Yang,

    1. Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
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  • Shannon McCall,

    1. Department of Pathology, Duke University Medical Center, Durham, North Carolina
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  • Jiawen Huang,

    1. Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
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  • Xing Xian Yu,

    1. Department of Antisense Drug Discovery, Isis Phamaceuticals, Inc., Carlsbad, California
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  • Sanjay K. Pandey,

    1. Department of Antisense Drug Discovery, Isis Phamaceuticals, Inc., Carlsbad, California
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  • Sanjay Bhanot,

    1. Department of Antisense Drug Discovery, Isis Phamaceuticals, Inc., Carlsbad, California
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    • Potential conflict of interest: Dr. Bhanot and Dr. Monia own stock at Isis Pharmaceuticals. Dr. Diehl received grants from Glaxo and Axscan.

  • Brett P. Monia,

    1. Department of Antisense Drug Discovery, Isis Phamaceuticals, Inc., Carlsbad, California
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    • Potential conflict of interest: Dr. Bhanot and Dr. Monia own stock at Isis Pharmaceuticals. Dr. Diehl received grants from Glaxo and Axscan.

  • Yin-Xiong Li,

    1. Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
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  • Anna Mae Diehl

    Corresponding author
    1. Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
    • Duke University Medical Center, Division of Gastroenterology, Snyderman GSRB I, Suite 1073, 595 LaSalle Street, Box 3256, Durham, NC 27710
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    • Potential conflict of interest: Dr. Bhanot and Dr. Monia own stock at Isis Pharmaceuticals. Dr. Diehl received grants from Glaxo and Axscan.

    • fax: 919-684-4183


Abstract

In the early stages of nonalcoholic fatty liver disease (NAFLD), triglycerides accumulate in hepatocytes. Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in hepatocyte triglyceride biosynthesis. DGAT2 antisense oligonucleotide (ASO) treatment improved hepatic steatosis dramatically in a previous study of obese mice. According to the 2-hit hypothesis for progression of NAFLD, hepatic steatosis is a risk factor for nonalcoholic steatohepatitis (NASH) and fibrosis. To evaluate this hypothesis, we inhibited DGAT2 in a mouse model of NASH induced by a diet deficient in methionine and choline (MCD). Six-week-old genetically obese and diabetic male db/db mice were fed either the control or the MCD diet for 4 or 8 weeks. The MCD diet group was treated with either 25 mg/kg DGAT2 ASO or saline intraperitoneally twice weekly. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress, and systemic insulin sensitivity were evaluated. Hepatic steatosis, necroinflammation, and fibrosis were increased in saline-treated MCD diet–fed mice compared to controls. Treating MCD diet–fed mice with DGAT2 ASO for 4 and 8 weeks decreased hepatic steatosis, but increased hepatic free fatty acids, cytochrome P4502E1, markers of lipid peroxidation/oxidant stress, lobular necroinflammation, and fibrosis. Progression of liver damage occurred despite reduced hepatic expression of tumor necrosis factor alpha, increased serum adiponectin, and striking improvement in systemic insulin sensitivity. Conclusion: Results from this mouse model would suggest accumulation of triglycerides may be a protective mechanism to prevent progressive liver damage in NAFLD. (HEPATOLOGY 2007.)

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