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

• Published in: Journal of lipid research Vol. 59; no. 10; pp. 1977 - 1986
• Main Authors: Peng, Kang-Yu, Watt, Matthew J., Rensen, Sander, Greve, Jan Willem, Huynh, Kevin, Jayawardana, Kaushala S., Meikle, Peter J., Meex, Ruth C.R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2018; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Adult; Cohort Studies; Disease Progression; Female; Humans; Lipid Metabolism; lipidomics; Liver - metabolism; Liver - pathology; Male; Middle Aged; mitochondria; Mitochondria - pathology; Non-alcoholic Fatty Liver Disease - blood; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; obesity; Patient-Oriented and Epidemiological Research; liver metabolism; mitochondria; lipidomics; obesity
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1194/jlr.M085613

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.