Hepatic Dysfunction Caused by Consumption of a High-Fat Diet

Abstract

SUMMARY Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver dysfunction and low-grade inflammation during the development of diet-induced metabolic syndrome. We validated these model findings with additional experiments on mouse liver sections. In total, we present an integrative systems biology study of diet-induced hepatic insulin resistance that uncovered molecular features promoting the development and maintenance of metabolic disease.

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

“…A comprehensive multiomics study identified hepatocyte apoptosis as a key early signaling event in high‐fat diet‐induced NASH in mice . In keeping with this observation, mice deficient in apoptosis are protected from NASH .…”

High‐fat diet in a mouse insulin‐resistant model induces widespread rewiring of the phosphotyrosine signaling network

“…To determine whether the in vivo effects of high‐fat diet (HFD) on mouse livers would mimic the in vitro effects of saturated fatty acids on hepatocytes, we used an established DIO model in C57BL/6J mice that has been shown to mirror hepatic dysfunction and signal transduction changes observed in patients (Collins et al , ; Soltis et al , ). Using a staggered HFD start to obtain an age‐matched end‐point, male mice were fed a normal chow diet (NC) or HFD for 6 or 16 weeks before euthanasia, liver resection, and analysis of the hepatic proteome and pTyr changes by LC‐MS/MS (Fig EV2A).…”

“…Proteins associated with lipid metabolism, transport, and ß‐oxidation included apolipoproteins, fatty acid binding proteins, and mitochondrial proteins [e.g., acetyl‐CoA acetyltransferase ACAT1 (THIL), acyl‐CoA dehydrogenase (ACADM); Fig D, left panel], whereas a large number (> 20) of cytochrome P450 family members was in the pool of proteins downregulated in HFD (Fig D, right panel). We assessed the general reliability of our data by benchmarking it against previously published liver proteomes (Ghose et al , ; Benard et al , ; Liu et al , ; Soltis et al , ; Krahmer et al , ). Enrichment of the top GO terms in the up‐ and downregulated sets are consistent with these reports, and, despite stringent protein filters which reduced the number of quantified proteins from ~5,200 to ~4,400, our protein numbers are well within the range of those studies (950–6,000).…”

“…The development of selective insulin resistance associated with high calorie diets and obesity has been well documented (Biddinger & Kahn, ; Brown & Goldstein, ; Titchenell et al , , ), but molecular features underpinning this process have been underexplored. Recently, “omics”‐type data sets were generated (Sabidó et al , ; Soltis et al , ; Krahmer et al , ; Li et al , ) using in vitro and in vivo models of fatty acid‐ and DIO‐induced insulin resistance that enable a much more comprehensive understanding of the complexity of this process by integrating genomics‐, metabolomics‐, and proteomics‐type information. Tyrosine phosphorylation and associated signaling cascades are an important layer of regulation of cell behavior and phenotypic changes.…”

“…Molecular and cellular models of diet‐induced insulin resistance are being explored to understand the complex tissue‐specific events during overnutrition that drive the progression of insulin resistance and diabetes. To that end, system‐level approaches have helped to elucidate the wide‐ranging alterations in protein, RNA, and metabolite levels associated with obesity, and may help open up novel avenues for therapeutic intervention (Sabidó et al , ; Soltis et al , ; Krahmer et al , ; Li et al , ). However, to date, only limited data on the fatty acid‐induced changes of basal hepatic phosphotyrosine networks have been collected, oftentimes relying on antibody detection of selected phosphorylation sites.…”