Maternal hepatic adaptations during obese pregnancy encompass lobe-specific mitochondrial alterations and oxidative stress.

Abstract

Maternal obesity(MO) is rising worldwide, affecting half of all gestations, constituting a risk-factor for pregnancy-associated liver diseases (PALD) and hepatic diseases. PALD occur in approximately 3% of pregnancies and are characterized by maternal hepatic oxidative stress(OS) and mitochondrial dysfunction. Understanding the role of MO on liver function and pathophysiology could be crucial for understanding the altered pathways leading to PALD and liver disease. We investigated specific hepatic metabolic alterations in mitochondria and oxidative stress during MO at late-gestation. Maternal hepatic tissue was collected at 90% gestation in Control and MO ewes. Maternal hepatic redox state, mitochondrial Respiratory Chain(MRC) and OS markers were investigated. MO decreased MRC complex-II activity and SDHA and SDHB protein, increased complex-I and complex-IV activities despite reduced mtCO1 protein, and increased ATP5a protein. Hepatic MO-metabolic remodeling was characterized by decreased ANT-1/2 and VDAC protein expression and PKA activity, and augmented NAD+/NADH ratio due to reduced NADH levels. MO showed an altered redox state with increased OS, increased lipid peroxidation, decreased GSH/GSSG ratio, increased SOD and decreased catalase antioxidant enzymatic activities, lower catalase, glutathione peroxidase (Gpx)-4 and glutathione reductase protein expression, and increased Gpx-1 abundance. MO-related hepatic changes were more evident in the right lobe, corroborated by the integrative data analysis. Hepatic tissue from obese pregnant ewes showed alterations in the redox state, consistent with OS and MRC and metabolism remodeling. These are hallmarks of PALD and hepatic disease, supporting MO as a risk-factor and highlighting OS and mitochondrial dysfunction as mechanisms responsible for liver disease predisposition.