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Mouse KLF11 regulates hepatic lipid metabolism

  • Huabing Zhang
    Affiliations
    National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Qi Chen
    Affiliations
    National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Min Yang
    Affiliations
    Department of Cardiology, Metabolic Diseases Hospital, Tianjin Medical University, Key Lab of Hormone and Development, Ministry of Health and Tianjin, Tianjin, China
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  • Bin Zhu
    Affiliations
    Department of General Surgery, Beijing Shijitan Hospital, Clinical Cancer Center of Capital Medical University, Beijing, China
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  • Ying Cui
    Affiliations
    National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Yuan Xue
    Affiliations
    National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Ning Gong
    Affiliations
    National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Anfang Cui
    Affiliations
    National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Min Wang
    Affiliations
    National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Lian Shen
    Affiliations
    National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Shutian Zhang
    Affiliations
    Beijing Friendship Hospital, Capital Medical University, Beijing Digestive Disease Center, Beijing Municipal Lab for Precancerous Lesion of Digestive Diseases, Beijing, China
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  • Fude Fang
    Affiliations
    National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Yongsheng Chang
    Correspondence
    Corresponding author. Address: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China. Tel.: +86 10 65296424; fax: +86 10 65253005.
    Affiliations
    National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Published:November 26, 2012DOI:https://doi.org/10.1016/j.jhep.2012.11.024

      Background & Aims

      Missense mutations in human Krüppel-like factor 11 (KLF11) lead to the development of diabetes, as a result of impaired insulin synthesis in the pancreas. However, the role of KLF11 in peripheral tissues is largely unknown. The aim of this study is to evaluate the role of KLF11 in the regulation of hepatic lipid homeostasis using different mouse models.

      Methods

      Adenoviruses expressing KLF11 (Ad-KLF11) or KLF11-specific shRNA (Ad-shKLF11) were injected into db/db diabetic, high-fat diet-induced obese (DIO), or normal C57BL/6J mice. Histological analysis of the fatty liver phenotype and biochemical analysis of hepatic and serum TG levels in these mice were performed. The molecular mechanism by which KLF11 regulates lipid metabolism in primary hepatocytes and mouse livers was explored.

      Results

      The expression of the transcription factor KLF11 gene is dysregulated in the livers of db/db and DIO mice. Adenovirus-mediated overexpression of KLF11 in the livers of db/db and DIO mice activates the PPARα signaling pathway, subsequently markedly improving the fatty liver phenotype. Conversely, knockdown of KLF11, by adenovirus (Ad-shKLF11) in livers of wild type C57BL/6J and db/m mice, increases hepatic triglyceride (TG) levels, owing to decreased fatty acid oxidation. Finally, the treatment of diabetic mice with Ad-shPPARα abolishes KLF11 stimulatory effects on the expression of genes involved in fatty acid oxidation and inhibitory effects on hepatic TG content. In contrast, PPARα rescue restores the increased hepatic TG levels in Ad-shKLF11-infected db/m mice to normal levels.

      Conclusions

      KLF11 is an important regulator of hepatic lipid metabolism.

      Abbreviations:

      ALT (alanine aminotransferase), AST (aspartate aminotransaminase), Col1α1 (collagen type 1α1), CPT1a (carnitine palmitoyl transferase 1a), CTGF (connective tissue growth factor), CYP4A10 and CYP4A14 (cytochrome P450 enzymes), DIO (diet-induced obese), FAS (fatty acid synthase), FBP1 (fructose bisphosphatase 1), GSK1 (glycogen synthase 1), G6pase (glucose-6-phosphatase), HF (high-fat), KLFs (Krüppel-like factors), KLF11 (Krüppel-like factor 11), MCAD (medium-chain acyl-CoA dehydrogenase), MODY (maturity-onset diabetes of the young), NAFLD (non-alcoholic fatty liver disease), PCR (polymerase chain reaction), PDK4 (pyruvate dehydrogenase kinase isoenzyme 4), Pdx-1 (pancreatic-duodenal homeobox-1), PEPCK (phosphoenol-pyruvate kinase), PGC-1α (PPAR-γ co-activator-1α), PPARα (peroxisome proliferator-activated receptor-α), qRT-PCR (quantitative real-time reverse-transcriptase PCR), shRNA (short-hairpin RNA), SREBP-1 (sterol regulatory element binding protein-1), TG (triglyceride), TGF-β (transforming growth factor β), UCP-1 (uncoupling protein 1), VLDL (very low density lipoprotein)

      Keywords

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