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 3

Flow cytometry of NHP fetal liver immune cells.

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Flow cytometry of NHP fetal liver immune cells. Nonlymphoid myeloid cell...
Nonlymphoid myeloid cells and lymphoid cells in CD (blue) and WSD (yellow) fetal liver mononuclear cells, as a proportion of total viable cells or cell subsets by flow cytometry; n = 4 CD and n = 7 WSD. (A) Nonlymphoid cells, defined as CD3–CD20–, as a proportion of total viable cells. (B) DCs (DC), myeloid DCs (mDC), and plasmacytoid DCs (pDC) as a proportion of total viable cells. (C) Monocytes and natural killer (NK) cells as a proportion of nonlymphoid cells. NK cell subsets as a proportion of NK cells (D) and monocyte subsets as a proportion of monocytes (E) characterized by presence (16+) or absence (16-) of CD16. (F) CD4+ T cells, CD8+ T cells, and CD20+ B cells as a proportion of total viable cells. (G) CD4+ T cell subsets as a proportion of CD4+ T cells, corresponding to naive (Na), central memory (CM), transitional effector memory (TEM), and effector memory (EM) T cells. (H) CD20+ B cell subsets as a proportion of CD20+ B cells, corresponding to other (Other), memory (MEM), marginal zone–like (Mz-like), and naive B cells. Unpaired 2-tailed Student’s t test was used to test significance for all cell types other than mDCs, which had values of 0 in the CD group, so an unpaired 1-tailed t test was performed with Welch’s correction. *P < 0.05.