Maternal Western Diet Is Associated With Distinct Preclinical Pediatric Nafld Phenotypes in Juvenile Nonhuman Primate Offspring

Authors

Michael J Nash
Evgenia Dobrinskikh
Rachel C Janssen
Mark A Lovell
Deborah A Schady
Claire Levek
Kenneth L Jones
Angelo D'Alessandro
Paul Kievit
Kjersti M Aagaard
Carrie E McCurdy
Maureen Gannon
Jacob E Friedman
Stephanie R Wesolowski

Language

English

Publication Date

2-1-2023

Journal

Hepatology Communications

DOI

10.1097/HC9.0000000000000014

PMID

36691970

PMCID

PMC9851700

PubMedCentral® Posted Date

1-18-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Pediatric NAFLD has distinct and variable pathology, yet causation remains unclear. We have shown that maternal Western-style diet (mWSD) compared with maternal chow diet (CD) consumption in nonhuman primates produces hepatic injury and steatosis in fetal offspring. Here, we define the role of mWSD and postweaning Western-style diet (pwWSD) exposures on molecular mechanisms linked to NAFLD development in a cohort of 3-year-old juvenile nonhuman primates offspring exposed to maternal CD or mWSD followed by CD or Western-style diet after weaning. We used histologic, transcriptomic, and metabolomic analyses to identify hepatic pathways regulating NAFLD. Offspring exposed to mWSD showed increased hepatic periportal collagen deposition but unchanged hepatic triglyceride levels and body weight. mWSD was associated with a downregulation of gene expression pathways underlying HNF4α activity and protein, and downregulation of antioxidant signaling, mitochondrial biogenesis, and PPAR signaling pathways. In offspring exposed to both mWSD and pwWSD, liver RNA profiles showed upregulation of pathways promoting fibrosis and endoplasmic reticulum stress and increased BiP protein expression with pwWSD. pwWSD increased acylcarnitines and decreased anti-inflammatory fatty acids, which was more pronounced when coupled with mWSD exposure. Further, mWSD shifted liver metabolites towards decreased purine catabolism in favor of synthesis, suggesting a mitochondrial DNA repair response. Our findings demonstrate that 3-year-old offspring exposed to mWSD but weaned to a CD have periportal collagen deposition, with transcriptional and metabolic pathways underlying hepatic oxidative stress, compromised mitochondrial lipid sensing, and decreased antioxidant response. Exposure to pwWSD worsens these phenotypes, triggers endoplasmic reticulum stress, and increases fibrosis. Overall, mWSD exposure is associated with altered expression of candidate genes and metabolites related to NAFLD that persist in juvenile offspring preceding clinical presentation of NAFLD.

Keywords

Animals, Non-alcoholic Fatty Liver Disease, Diet, Western, Antioxidants, Fibrosis, Phenotype, Primates

Published Open-Access

yes

Recommended Citation

Nash, Michael J; Dobrinskikh, Evgenia; Janssen, Rachel C; et al., "Maternal Western Diet Is Associated With Distinct Preclinical Pediatric Nafld Phenotypes in Juvenile Nonhuman Primate Offspring" (2023). Faculty and Staff Publications. 5630.
https://digitalcommons.library.tmc.edu/baylor_docs/5630