Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice
Dario F. De Jesus, … , Jussi Pihlajamäki, Rohit N. Kulkarni
Dario F. De Jesus, … , Jussi Pihlajamäki, Rohit N. Kulkarni
Published April 6, 2020
Citation Information: J Clin Invest. 2020;130(5):2391-2407. https://doi.org/10.1172/JCI127502.
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Research Article Development Hepatology

Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice

Abstract

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 pathway, 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.

Authors

Dario F. De Jesus, Kazuki Orime, Dorota Kaminska, Tomohiko Kimura, Giorgio Basile, Chih-Hao Wang, Larissa Haertle, Renzo Riemens, Natalie K. Brown, Jiang Hu, Ville Männistö, Amélia M. Silva, Ercument Dirice, Yu-Hua Tseng, Thomas Haaf, Jussi Pihlajamäki, Rohit N. Kulkarni

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Figure 6

NREP relevance in human hepatic steatosis.

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NREP relevance in human hepatic steatosis. (A) NREP knockdown in human p...
(A) NREP knockdown in human primary hepatocytes (n = 3 independent experiments, hepatocytes from 5 pooled healthy donors). (B) Representative oil red staining showing lipid droplets in human primary hepatocytes treated with BSA or challenged with palmitate for 24 hours (n = 3 independent experiments; original magnification, ×400; scale bar: 50 μm). (C) Quantification of oil red staining intensity (n = 3 independent experiments). (D) RT-PCR analyses of genes involved in β-oxidation (PPARα), transcriptional regulation of fatty acid (PPARγ, SREBP1c) and cholesterol (SREBP2) metabolism, and acyl-CoA (ACLY) and cholesterol synthesis (HMGCR) (n = 3 independent experiments, hepatocytes from 5 pooled healthy donors). (E and F) NREP protein (E) and mRNA (F) levels in human liver samples from controls and patients with steatosis (control, n = 7; steatosis, n = 8; Supplemental Table 6). (G) Hepatic mRNA levels in controls and steatosis and steatohepatitis patients by microarrays (GSE33814). (H) Pearson’s correlations between NREP and ACLY mRNA levels in all groups in controls, steatosis, and steatohepatitis. Significance in comparisons between 2 groups was determined by 2-way ANOVA with Holm-Šidák multiple-comparisons test in A, 1-way ANOVA with Holm-Šidák multiple-comparisons test in C and D, 2-tailed unpaired t test in F, Benjamini-Hochberg method (see Methods) in G, and Pearson’s correlations in H. *P < 0.05; **P < 0.01; ***P < 0.001. All data are shown as mean ± SEM.