Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice
| Autor: | Ercument Dirice, Jiang Hu, Amélia M. Silva, Natalie K. Brown, Larissa Haertle, Dorota Kaminska, Thomas Haaf, Chih-Hao Wang, Tomohiko Kimura, Rohit N. Kulkarni, Ville Männistö, Dario F. De Jesus, Renzo Riemens, Yu-Hua Tseng, Kazuki Orime, Jussi Pihlajamäki, Giorgio Basile |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Offspring Gene Expression Regulation Enzymologic Epigenesis Genetic Mice 03 medical and health sciences 0302 clinical medicine Insulin resistance Downregulation and upregulation Non-alcoholic Fatty Liver Disease Pregnancy Internal medicine Nonalcoholic fatty liver disease medicine Animals Epigenetics Metabolic Syndrome Mice Knockout biology General Medicine Lipid Metabolism medicine.disease 3. Good health Insulin receptor 030104 developmental biology Endocrinology Prenatal Exposure Delayed Effects 030220 oncology & carcinogenesis biology.protein Female Steatosis Metabolic syndrome Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci127502 |
| Popis: | The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Although gene-environment interactions have been implicated in the etiology of several disorders, the impact of paternal and/or maternal metabolic syndrome on the clinical phenotypes of offspring and the underlying genetic and epigenetic contributors of NAFLD have not been fully explored. To this end, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique nondietary model manifesting 3 hallmarks that confer high risk for the development of NAFLD: hyperglycemia, insulin resistance, and dyslipidemia. We report that parental metabolic syndrome epigenetically reprograms members of the TGF-β family, including neuronal regeneration-related protein (NREP) and growth differentiation factor 15 (GDF15). NREP and GDF15 modulate the expression of several genes involved in the regulation of hepatic lipid metabolism. In particular, NREP downregulation increases the protein abundance of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and ATP-citrate lyase (ACLY) in a TGF-β receptor/PI3K/protein kinase B-dependent manner, to regulate hepatic acetyl-CoA and cholesterol synthesis. Reduced hepatic expression of NREP in patients with NAFLD and substantial correlations between low serum NREP levels and the presence of steatosis and nonalcoholic steatohepatitis highlight the clinical translational relevance of our findings in the context of recent preclinical trials implicating ACLY in NAFLD progression. |
| Databáze: | OpenAIRE |
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