Maternal Western diet exposure increases periportal fibrosis beginning in utero in nonhuman primate offspring
Michael J. Nash, … , Jacob E. Friedman, Stephanie R. Wesolowski
Michael J. Nash, … , Jacob E. Friedman, Stephanie R. Wesolowski
Published December 22, 2021
Citation Information: JCI Insight. 2021;6(24):e154093. https://doi.org/10.1172/jci.insight.154093.
View: Text | PDF
Research Article Gastroenterology

Maternal Western diet exposure increases periportal fibrosis beginning in utero in nonhuman primate offspring

Abstract

Maternal obesity affects nearly one-third of pregnancies and is a major risk factor for nonalcoholic fatty liver disease (NAFLD) in adolescent offspring, yet the mechanisms behind NAFLD remain poorly understood. Here, we demonstrate that nonhuman primate fetuses exposed to maternal Western-style diet (WSD) displayed increased fibrillar collagen deposition in the liver periportal region, with increased ACTA2 and TIMP1 staining, indicating localized hepatic stellate cell (HSC) and myofibroblast activation. This collagen deposition pattern persisted in 1-year-old offspring, despite weaning to a control diet (CD). Maternal WSD exposure increased the frequency of DCs and reduced memory CD4+ T cells in fetal liver without affecting systemic or hepatic inflammatory cytokines. Switching obese dams from WSD to CD before conception or supplementation of the WSD with resveratrol decreased fetal hepatic collagen deposition and reduced markers of portal triad fibrosis, oxidative stress, and fetal hypoxemia. These results demonstrate that HSCs and myofibroblasts are sensitive to maternal WSD-associated oxidative stress in the fetal liver, which is accompanied by increased periportal collagen deposition, indicative of early fibrogenesis beginning in utero. Alleviating maternal WSD-driven oxidative stress in the fetal liver holds promise for halting steatosis and fibrosis and preventing developmental programming of NAFLD.

Authors

Michael J. Nash, Evgenia Dobrinskikh, Sean A. Newsom, Ilhem Messaoudi, Rachel C. Janssen, Kjersti M. Aagaard, Carrie E. McCurdy, Maureen Gannon, Paul Kievit, Jacob E. Friedman, Stephanie R. Wesolowski

×

Figure 7

Effects of resveratrol on NHP fetal hepatic oxidative stress proteins.

Options: View larger image (or click on image) Download as PowerPoint
Effects of resveratrol on NHP fetal hepatic oxidative stress proteins. Q...
Quantitation (A) and representative Western blot images (B) of oxidative stress proteins. JNK and pJNK bands were identified and quantified within the 46–54 kDa range. n = 7–12 CD, n = 10–18 WSD, and n = 6–7 RESV. ANOVA with fixed effect for maternal diet is shown and is significant for all variables shown (P < 0.05), unless noted otherwise. Individual post test comparisons are indicated as different letters. Bars with different symbols or letters represent groups with significant (P < 0.05) differences from one another, and bars sharing the same letter are not different from one another. (C) Correlation coefficients for portal triad SHG signal area vs. umbilical artery cord blood measurements, using Pearson correlation coefficient to obtain the P values listed. *P < 0.05, **P < 0.005. (D) SHG area vs. umbilical artery pO2 measurements in CD (blue), WSD (yellow), DR (green), and RESV (purple) groups. (E) Maternal WSD increases hypoxia, fetal hepatic steatosis, oxidative stress and activation of hepatic stellate cells and myofibroblast formation in the portal zone. Dendritic cells are recruited in increased amounts to the fetal liver. The effects on liver steatosis and collagen formation were prevented by switching obese WSD-fed females to control diet prior to pregnancy and by supplementing obese WSD-fed females with resveratrol. Image created with BioRender.