Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide and few studies have associated maternal diabetes and birth weights with increased risk for NAFLD. We used an unique non-dietary model, manifesting hyperglycemia and hyperinsulinemia-two hallmarks of gestational and type 2 diabetes. We aimed to determine the genetic and epigenetic effects of paternal vs. maternal genetic insulin resistance on the developmental programming in the offspring of the liver-specific insulin receptor knockout (LIRKO) mice. Male control F1 offspring from father LIRKO (FL), mother LIRKO (ML) or control mothers and fathers (C) were weaned on a chow or high-fat-diet (HFD) and followed for 3 months. FL and ML showed impaired growth and body weight composition. FL and ML developed hepatic steatosis compared to C when challenged with HFD and exhibited increased hepatic expression of lipogenesis-associated genes. Hepatic transcriptomic and genome-wide DNA methylation analyses of FL and ML on chow diet presented enriched-pathways associated with TGF-β signaling and lipid synthesis. FL and ML hepatic NREP mRNA levels were decreased 50% (p<0.05) on HFD compared to C. In-vivo and in-vitro modeling of hepatic steatosis in HepG2 and human primary hepatocytes decreased NREP mRNA and protein levels. Knock-down experiments performed in HepG2 cells revealed that NREP acts by regulating triglyceride and cholesterol synthesis transcriptional network via regulation of ATP-citrate lyase (ACL) in a phospho-AKT dependent manner. Finally, reduced NREP mRNA levels in patients with hepatic steatosis by 40% (p<0.05) and recent preclinical trials implicating ACL in NAFLD highlight the translation relevance of our findings. These data suggest that prenatal insulin resistance epigenetically regulates a novel gene, NREP, that has detrimental effects on metabolic adaptation and transcriptional regulation of hepatic metabolism in the development of NAFLD.
D.F. De Jesus: None. K. Orime: None. C. Wang: None. J. Hu: None. E. Dirice: None. A.M. Silva: None. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd.. Research Support; Self; MedImmune. J. Pihlajamaki: None. R. Kulkarni: None.