Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men

被引:29
作者
Fahlbusch, Pia [1 ,2 ]
Knebel, Birgit [1 ,2 ]
Hoerbelt, Tina [1 ,2 ]
Barbosa, David Monteiro [1 ,2 ]
Nikolic, Aleksandra [1 ,2 ]
Jacob, Sylvia [1 ,2 ]
Al-Hasani, Hadi [1 ,2 ,3 ]
Van de Velde, Frederique [4 ]
Van Nieuwenhove, Yves [5 ]
Mueller-Wieland, Dirk [6 ]
Lapauw, Bruno [4 ]
Ouwens, D. Margriet [1 ,2 ,4 ]
Kotzka, Jorg [1 ,2 ]
机构
[1] Heinrich Heine Univ Dusseldorf, German Diabet Ctr DDZ, Inst Clin Biochem & Pathobiochem, Leibniz Ctr Diabet Res, Aufm Hennekamp 65, D-40225 Dusseldorf, Germany
[2] German Ctr Diabet Res DZD, D-85764 Munich, Germany
[3] Heinrich Heine Univ, Med Fac, German Diabet Ctr DDZ, Inst Clin Biochem & Pathobiochem, D-40225 Dusseldorf, Germany
[4] Ghent Univ Hosp, Dept Endocrinol, B-9000 Ghent, Belgium
[5] Ghent Univ Hosp, Dept Gastrointestinal Surg, B-9000 Ghent, Belgium
[6] Univ Hosp Aachen, Clin Res Ctr, Dept Internal Med 1, D-52074 Aachen, Germany
关键词
NAFLD; fatty liver metabolism; fatty liver progression; de novo lipogenesis; IGFBP2; IGF system; methylation; SREBP-1c; INSULIN-RESISTANCE; LIPID-METABOLISM; REDUCED EXPRESSION; SCORING SYSTEM; ADIPOSE-TISSUE; DISEASE; OBESITY; LIPOTOXICITY; PATHOGENESIS; CHOLESTEROL;
D O I
10.3390/ijms21114144
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Fatty liver occurs from simple steatosis with accumulated hepatic lipids and hepatic insulin resistance to severe steatohepatitis, with aggravated lipid accumulation and systemic insulin resistance, but this progression is still poorly understood. Analyses of hepatic gene expression patterns from alb-SREBP-1c mice with moderate, or aP2-SREBP-1c mice with aggravated, hepatic lipid accumulation revealed IGFBP2 as key nodal molecule differing between moderate and aggravated fatty liver. Reduced IGFBP2 expression in aggravated fatty liver was paralleled with promoter hypermethylation, reduced hepatic IGFBP2 secretion and IGFBP2 circulating in plasma. Physiologically, the decrease of IGFBP2 was accompanied with reduced fatty acid oxidation and increased de novo lipogenesis potentially mediated by IGF1 in primary hepatocytes. Furthermore, methyltransferase and sirtuin activities were enhanced. In humans, IGFBP2 serum concentration was lower in obese men with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) compared to non-obese controls, and liver fat reduction by weight-loss intervention correlated with an increase of IGFBP2 serum levels. In conclusion, hepatic IGFBP2 abundance correlates to its circulating level and is related to hepatic energy metabolism and de novo lipogenesis. This designates IGFBP2 as non-invasive biomarker for fatty liver disease progression and might further provide an additional variable for risk prediction for pathogenesis of fatty liver in diabetes subtype clusters.
引用
收藏
页码:1 / 18
页数:18
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