Transcriptome changes in stages of non-alcoholic fatty liver disease

Abstract

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and globally. The currently understood model of pathogenesis consists of a ‘multiple hit’ hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury. AIM To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis (NASH) tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis. METHODS We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology. For NAFLD, we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies; for NASH, we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies. RESULTS Our results from the NAFLD analysis reinforce the role of altered metabolism, inflammation, and cell survival in pathogenesis and support recently described contributors to disease activity, such as altered androgen and long non-coding RNA activity. The top upstream regulator was found to be sterol regulatory element binding transcription factor 1 (SREBF1), a transcription factor involved in lipid homeostasis. Downstream of SREBF1, we observed upregulation in CXCL10, HMGCR, HMGCS1, fatty acid binding protein 5, paternally expressed imprinted gene 10, and downregulation of sex hormone-binding globulin and insulin-like growth factor 1. These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver. Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis. Top canonical pathways, disease networks, and disease functions were related to cholesterol synthesis, lipid metabolism, adipogenesis, and metabolic disease. Top upstream regulators included pro-inflammatory cytokines tumor necrosis factor and IL1B, PDGF BB, and beta-estradiol. Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism, extracellular matrix deposition, and tumor suppression. Lastly, we found riciribine (an AKT inhibitor) and ZSTK-474 (a PI3K inhibitor) as potential drugs that targeted the differential gene expression in our dataset. CONCLUSION In this study we describe several molecular processes that may correlate with NAFLD disease and progression. We also identified ricirbine and ZSTK-474 as potential therapy.

Effect of Donor Age and Liver Steatosis on Potential of Decellularized Liver Matrices to be used as a Platform for iPSC‐Hepatocyte Culture

“…Compared to normal (<5% steatosis) livers, they noted upregulation in FABP5 along with other genes involved in lipogenesis. [ 38 ] Other studies [ 39,40 ] have also shown a strong correlation between fat accumulation in the liver and the upregulation of FABP5, ACSL4, and ACACA. The observation of a similar increase in these factors in primary human hepatocytes suggests that excess fat remaining on ECM collected from highly steatotic livers may lead to a NAFLD‐like phenotype in liver cells.…”

Polyunsaturated and Saturated Oxylipin Plasma Levels Allow Monitoring the Non-Alcoholic Fatty Liver Disease Progression to Severe Stages

“…The higher glycemia observed in the group of patients with severe NAFLD probably evidences a worsening of insulin resistance at this stage of the disease. The metabolic pathways involved in NAFLD progression are not well characterized, but low-grade chronic inflammation and oxidative stress take part in the pathogenesis and progression of NAFLD [ 46 , 47 ]. MDA, the PUFA peroxidation marker of oxidative stress [ 48 ], is progressively increased with the stage of NAFLD, and its plasma levels are significantly correlated with the IFC, reflecting that low-grade oxidative stress is secondary to the accumulation of fatty acids in the liver.…”

“…Intrahepatic lipid saturation predisposes the liver to inflammation; however, the mechanisms by which this intrahepatic lipid saturation promotes NAFLD progression are still poorly understood [ 46 ]. The obtained data show that the plasma levels of 12HEST and 17HDoHE are the lipid mediators with the highest correlation with the intrahepatic fat content in NAFLD patients.…”

PI3K/AKT/SERBP-1 pathway regulates Alisma orientalis beverage treatment of atherosclerosis in APOE −/− high-fat diet mice

“…Recent studies showed that PI3K/AKT signaling is significantly upregulated in patients with nonalcoholic fatty liver disease, one of the risk factors for AS, and inhibitors against PI3K and AKT have potential regulatory effects on lipid metabolism (Aljabban et al. 2022 ). Our results showed that phosphorylation of the PI3K/AKT signaling pathway in the liver of AS model mice is significantly activated, resulting in elevated SREBPs.…”