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Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) comprises fat-accumulating conditions within hepatocytes that can cause severe liver damage and metabolic comorbidities. Studies suggest that mitochondrial dysfunction contributes to its development and progression and that the hepatic lipidome changes extensively in obesity and in NAFLD. To gain insight into the relationship between lipid metabolism and disease progression through different stages of NAFLD, we performed lipidomic analysis of plasma and liver biopsy samples from obese patients with nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) and from those without NAFLD. Congruent with earlier studies, hepatic lipid levels overall increased with NAFLD. Lipid species that differed with NAFLD severity were related to mitochondrial dysfunction; specifically, hepatic cardiolipin and ubiquinone accumulated in NAFL, and levels of acylcarnitine increased with NASH. We propose that increased levels of cardiolipin and ubiquinone may help to preserve mitochondrial function in early NAFLD, but that mitochondrial function eventually fails with progression to NASH, leading to increased acylcarnitine. We also found a negative association between hepatic odd-chain phosphatidylcholine and NAFLD, which may result from mitochondrial dysfunction-related impairment of branched-chain amino acid catabolism. Overall, these data suggest a close link between accumulation of specific hepatic lipid species, mitochondrial dysfunction, and the progression of NAFLD.

SUBMITTER: Peng KY

PROVIDER: S-EPMC6168306 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression.

Peng Kang-Yu KY Watt Matthew J MJ Rensen Sander S Greve Jan Willem JW Huynh Kevin K Jayawardana Kaushala S KS Meikle Peter J PJ Meex Ruth C R RCR

Journal of lipid research 20180724 10

Nonalcoholic fatty liver disease (NAFLD) comprises fat-accumulating conditions within hepatocytes that can cause severe liver damage and metabolic comorbidities. Studies suggest that mitochondrial dysfunction contributes to its development and progression and that the hepatic lipidome changes extensively in obesity and in NAFLD. To gain insight into the relationship between lipid metabolism and disease progression through different stages of NAFLD, we performed lipidomic analysis of plasma and l ...[more]

PMID: 30042157

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Project description:BackgroundNonalcoholic fatty liver disease (NAFLD) is now the major contributor to chronic liver disease. Disorders of lipid metabolism are a major element in the emergence of NAFLD. This research intended to explore lipid metabolism-related clusters in NAFLD and establish a prediction biomarker.MethodsThe expression mode of lipid metabolism-related genes (LMRGs) and immune characteristics in NAFLD were examined. The "ConsensusClusterPlus" package was utilized to investigate the lipid metabolism-related subgroup. The WGCNA was utilized to determine hub genes and perform functional enrichment analysis. After that, a model was constructed by machine learning techniques. To validate the predictive effectiveness, receiver operating characteristic curves, nomograms, decision curve analysis (DCA), and test sets were used. Lastly, gene set variation analysis (GSVA) was utilized to investigate the biological role of biomarkers in NAFLD.ResultsDysregulated LMRGs and immunological responses were identified between NAFLD and normal samples. Two LMRG-related clusters were identified in NAFLD. Immune infiltration analysis revealed that C2 had much more immune infiltration. GSVA also showed that these two subtypes have distinctly different biological features. Thirty cluster-specific genes were identified by two WGCNAs. Functional enrichment analysis indicated that cluster-specific genes are primarily engaged in adipogenesis, signalling by interleukins, and the JAK-STAT signalling pathway. Comparing several models, the random forest model exhibited good discrimination performance. Importantly, the final five-gene random forest model showed excellent predictive power in two test sets. In addition, the nomogram and DCA confirmed the precision of the model for NAFLD prediction. GSVA revealed that model genes were down-regulated in several immune and inflammatory-related routes. This suggests that these genes may inhibit the progression of NAFLD by inhibiting these pathways.ConclusionsThis research thoroughly emphasized the complex relationship between LMRGs and NAFLD and established a five-gene biomarker to evaluate the risk of the lipid metabolism phenotype and the pathologic results of NAFLD.

Dataset Information

Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression.

Publications

Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression.

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