Adverse Maternal Environment and Postweaning Western Diet Alter Hepatic CD36 Expression and Methylation Concurrently with Nonalcoholic Fatty Liver Disease in Mouse Offspring

Qi Fu; Paula E North; Xingrao Ke; Yi-Wen Huang; Katie A Fritz; Amber V Majnik; Robert H Lane

doi:10.1093/jn/nxab249

Adverse Maternal Environment and Postweaning Western Diet Alter Hepatic CD36 Expression and Methylation Concurrently with Nonalcoholic Fatty Liver Disease in Mouse Offspring

J Nutr. 2021 Oct 1;151(10):3102-3112. doi: 10.1093/jn/nxab249.

Authors

Qi Fu¹, Paula E North², Xingrao Ke¹, Yi-Wen Huang³, Katie A Fritz⁴, Amber V Majnik⁴, Robert H Lane⁵

Affiliations

¹ Department of Research Administration, Children's Mercy Hospital, Kansas City, MO, USA.
² Department of Pediatric Pathology, Medical College of Wisconsin, Milwaukee, WI, USA.
³ Department of Obstetrics & Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA.
⁴ Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
⁵ Department of Administration, Children's Mercy Hospital, Kansas City, MO, USA.

Abstract

Background: The role of an adverse maternal environment (AME) in conjunction with a postweaning Western diet (WD) in the development of nonalcoholic fatty liver disease (NAFLD) in adult offspring has not been explored. Likewise, the molecular mechanisms associated with AME-induced NAFLD have not been studied. The fatty acid translocase or cluster of differentiation 36 (CD36) has been implicated to play a causal role in the pathogenesis of WD-induced steatosis. However, it is unknown if CD36 plays a role in AME-induced NAFLD.

Objective: This study was designed to evaluate the isolated and additive impact of AME and postweaning WD on the expression and DNA methylation of hepatic Cd36 in association with the development of NAFLD in a novel mouse model.

Methods: AME constituted maternal WD and maternal stress, whereas the control (Con) group had neither. Female C57BL/6J mice were fed a WD [40% fat energy, 29.1% sucrose energy, and 0.15% cholesterol (wt/wt)] 5 wk prior to pregnancy and throughout lactation. Non invasive variable stressors (random frequent cage changing, limited bedding, novel object, etc.) were applied to WD dams during the last third of pregnancy to produce an AME. Con dams consumed the control diet (CD) (10% fat energy, no sucrose or cholesterol) and were not exposed to stress. Male offspring were weaned onto either CD or WD, creating 4 experimental groups: Con-CD, Con-WD, AME-CD, and AME-WD, and evaluated for metabolic and molecular parameters at 120 d of age.

Results: AME and postweaning WD independently and additively increased the development of hepatic steatosis in adult male offspring. AME and WD independently and additively upregulated hepatic CD36 protein and mRNA expression and hypomethylated promoters 2 and 3 of the Cd36 gene.

Conclusions: Using a mouse AME model together with postweaning WD, this study demonstrates a role for CD36 in AME-induced NAFLD in offspring and reveals 2 regions of environmentally induced epigenetic heterogeneity within Cd36.

Keywords: CD36; DNA; NAFLD; maternal environment; methylation; perinatal.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA Methylation
Diet, High-Fat / adverse effects
Diet, Western / adverse effects
Female
Liver / metabolism
Male
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / etiology
Non-alcoholic Fatty Liver Disease* / metabolism
Pregnancy