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.
Highlights
Obesity rates continue to increase and have reached epidemic proportions around the globe [1]
We demonstrate that maternal Western-style diet (WSD) exposure is associated with fibrillar collagen deposition and classic hepatic stellate cell (HSC) and myofibroblast activation markers in the portal zone in nonhuman primate (NHP) fetal liver
Our data further demonstrate that preventing WSD-induced oxidative stress in obese mothers either by diet switching or resveratrol treatment reduced collagen deposition and triglyceride content and attenuated markers of HSC activation in the fetal liver
Summary
Obesity rates continue to increase and have reached epidemic proportions around the globe [1]. Accompanying maternal obesity is an increase in noncommunicable metabolic disorders in children, leading to a body of literature that suggests that metabolic disorders, including obesity, type 2 diabetes mellitus, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD), are often of intrauterine origin [4,5,6]. NAFLD is the most common liver disease worldwide; it affects nearly 40% of obese youth and up to 10% of the general pediatric population [7]. NAFLD is characterized by steatosis (excess liver fat) that over time may progress to nonalcoholic steatohepatitis (NASH), with accompanying inflammation and fibrosis, leading to cirrhosis and increased risk for hepatocellular carcinoma [8]. NAFLD can progress rapidly in children, leading to end-stage liver disease and liver transplantation in early adulthood or sooner [4, 9] for reasons that remain poorly understood
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