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

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Figure 6

Effects of maternal diet interventions on NHP fetal hepatic collagen deposition.

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Effects of maternal diet interventions on NHP fetal hepatic collagen dep...
SHG signal intensity (A) and area (B) in portal triad regions from diet reversal (DR; green) and resveratrol (RESV; purple) fetal livers compared with mean of CD (blue dashed line) and WSD (yellow dashed line) groups; n = 4–5 DR and n = 5 RESV. RNAscope quantification of ACTA2+ (C) and TIMP1+ cells (D), and ACTA2 and TIMP1 double-positive cells (E) per portal triads in DR and RESV fetuses, compared with mean of CD (blue dashed line) and WSD (yellow dashed line) groups; n = 4 DR and n = 3 RESV. Expression of COL1A1 (F), COL3A1 (G), LGALS3 (H), and FAP (I) in DR and RESV fetal liver tissue, compared with mean of CD (blue dashed line) and WSD (yellow dashed line) groups; n = 20 CD, n = 26 WSD, n = 5 DR, and n = 7 RESV. †P < 0.05 vs. WSD and NS vs. CD; ‡P < 0.05 vs. CD and NS vs. WSD (by 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 symbols). Unmarked bars indicate NS P values for CD and WSD comparison. (J) TBARS of CD (blue), WSD (yellow), DR, and RESV livers; n = 5 CD, n = 7 WSD, n = 5 DR, and n = 6 RESV. (K) Glutamate to serine + glycine (Glu/[Ser+Gly]) ratio of CD, WSD, DR, and RESV livers; n = 5 CD, n = 6 WSD, n = 5 DR, and n = 3 RESV. (J and K) 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.