Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD.

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

“…While hepatocyte abnormalities in cytoplasmic lipid metabolism are commonly observed in NAFLD (Fabbrini et al, 2010b), the role of mitochondrial metabolism, which governs oxidative disposal of fats is less clear in NAFLD pathogenesis. Abnormalities of mitochondrial metabolism occur in and contribute to NAFLD/NASH pathogenesis (Hyotylainen et al, 2016; Serviddio et al, 2011; Serviddio et al, 2008; Wei et al, 2008). There is general (Felig et al, 1974; Iozzo et al, 2010; Koliaki et al, 2015; Satapati et al, 2015; Satapati et al, 2012; Sunny et al, 2011) but not uniform (Koliaki and Roden, 2013; Perry et al, 2016; Rector et al, 2010) consensus that, prior to the development of bona fide NASH, hepatic mitochondrial oxidation, and in particular fat oxidation, is augmented in obesity, systemic insulin resistance, and NAFLD.…”

Pathophysiology of Non Alcoholic Fatty Liver Disease

“…Both pathways are increased in NAFLD, even in non-diabetic patients, contributing to the synthesis of hepatic triglycerides and the promotion of hepatic steatosis [92]. In addition, patients with NAFLD have increased hepatic synthesis of palmitate through DNL, and this increases the risk of lipotoxicity and cell damage [25,93].…”

Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

“…Studies in animals (e.g., Sunny et al (15) ) have also been inconclusive because they compare age-matched animals treated with a high-fat diet (versus chow diet) without accounting for the increase in IR. In addition to BCAAs and AAAs, other AAs, such as glutamate, glutamine, alanine, and aspartate, have been found to be positively associated with increased cardiometabolic risk and particularly with Hep-IR, (12,(17)(18)(19) while glycine and serine were found decreased in metabolic diseases, including NAFLD. (19)(20)(21)(22)(23) Thus, the first aim of our study was to evaluate if plasma AA concentrations were increased/decreased similarly in subjects with and without obesity but with NAFLD and their association with the degree of fasting Hep-IR and peripheral IR.…”

“…In addition to BCAAs and AAAs, other AAs, such as glutamate, glutamine, alanine, and aspartate, have been found to be positively associated with increased cardiometabolic risk and particularly with Hep-IR, (12,(17)(18)(19) while glycine and serine were found decreased in metabolic diseases, including NAFLD. (19)(20)(21)(22)(23) Thus, the first aim of our study was to evaluate if plasma AA concentrations were increased/decreased similarly in subjects with and without obesity but with NAFLD and their association with the degree of fasting Hep-IR and peripheral IR. Our second aim was to evaluate if alterations in plasma AA concentrations (such as BCAAs, AAAs, glutamate, glycine, and serine), which alter cell function or are involved in mitochondrial function and oxidative stress, might reflect hepatic inflammation and/ or fibrosis.…”