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 3

Hepatic transcriptome of NAFLD-primed offspring reveals Nrep and Gdf15.

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Hepatic transcriptome of NAFLD-primed offspring reveals Nrep and Gdf15. ...
(A) H&E-stained liver sections from offspring on chow diet (original magnification, ×200; scale bar: 200 μm). (B) Hepatic triglyceride content in chow-diet offspring. (C) Hepatic cholesterol content in chow-diet offspring. Selected-pathway analyses of differentially expressed genes. (D) H&E-stained liver sections from offspring on HFD (original magnification, ×200; scale bar: 200 μm). (E) Hepatic triglyceride content in HFD offspring. (F) Hepatic cholesterol content in HFD offspring. (G) Volcano plot RNA sequencing representation of differently expressed genes (chow: control, n = 4; FL, n = 3; ML, n = 3). (H) Heatmap representation of the most significantly altered genes. (I) Selected-pathway analyses of altered genes in FL and ML compared with controls. (J and K) Hepatic Nrep gene expression analyses by quantitative PCR (qPCR) on chow (J) and HFD (K) at 12 weeks of age (chow and HFD: n = 4 litters/group). (L) Hepatic Nrep mRNA by qPCR in mice challenged with a 6-week low-fat diet (LFD) and HFD at 12 weeks of age (LFD and HFD: n = 5, diet intervention of 6 weeks). (M and N) Hepatic Nrep mRNA levels by qPCR in ob/ob (M) and db/db mice (N) at 12 weeks of age (n = 5 per group). (O and P) Hepatic Nrep gene expression analyses by qPCR in FL, ML, and controls on chow (O) and HFD (P) (chow and HFD: n = 4 litters/group). (Q) Hepatic Nrep mRNA by qPCR in mice challenged with a 6-week LFD and HFD (LFD and HFD: n = 5, diet intervention of 6 weeks). (R and S) Hepatic Nrep mRNA levels by qPCR in ob/ob (R) and db/db mice (S) at 12 weeks of age (n = 5). Unless otherwise stated: chow: control, n = 8, 3 litters; FL, n = 11, 4 litters; ML, n = 5, 3 litters; HFD: control, FL, and ML, n = 6, 3 litters per group. RNA sequencing data were based on control (n = 4 mice/litters), FL (n = 3 mice/litters), and ML (n = 3 mice/litters). One-way ANOVA with Holm-Šidák multiple-comparisons test; 2-tailed unpaired t test in L–N and Q–S. *P < 0.05; **P < 0.01; ***P < 0.001. In H, asterisk indicates FDR < 0.25 in FL and FDR < 0.10 in ML and FL/ML comparisons.