APA
Click to copy
Jesus, D. F. D., Orime, K., Kamińska, D., Kimura, T., Basile, G., Wang, C.-H., … Kulkarni, R. (2020). Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice. Journal of Clinical Investigation.
Chicago/Turabian
Click to copy
Jesus, Dario F. De, K. Orime, D. Kamińska, Tomohiko Kimura, G. Basile, Chih-Hao Wang, Larissa Haertle, et al. “Parental Metabolic Syndrome Epigenetically Reprograms Offspring Hepatic Lipid Metabolism in Mice.” Journal of Clinical Investigation (2020).
MLA
Click to copy
Jesus, Dario F. De, et al. “Parental Metabolic Syndrome Epigenetically Reprograms Offspring Hepatic Lipid Metabolism in Mice.” Journal of Clinical Investigation, 2020.
BibTeX Click to copy
@article{dario2020a,
title = {Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice.},
year = {2020},
journal = {Journal of Clinical Investigation},
author = {Jesus, Dario F. De and Orime, K. and Kamińska, D. and Kimura, Tomohiko and Basile, G. and Wang, Chih-Hao and Haertle, Larissa and Riemens, Renzo J M and Brown, Natalie K and Hu, Jiang and Männistö, V. and Silva, A. and Dirice, E. and Tseng, Y. and Haaf, T. and Pihlajamäki, J. and Kulkarni, R.}
}
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.