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Distinct Human Hepatocyte Lipidomics Profiles for Nonalcoholic Steatohepatitis and In Vitro-Induced Steatosis

ABSTRACT: Nonalcoholic steatohepatitis (NASH) is a severe form of steatotic liver injury that can be caused by a variety of stimuli and has a significant mortality rate. A common technique to induce in vitro steatosis involves culturing primary human hepatocytes (PHH) in a fatty acid-enriched media. This study compared the lipidome of PHH cultured in a fatty acid-enriched media to hepatocytes from patients with NASH and healthy controls to determine whether such culture techniques could generate a hepatocellular lipid profile similar to that observed in NASH patients. LC-MS lipidomics analysis of hepatocytes from patients with NASH revealed increases in the total cellular abundance of glycerolipids, phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylinositols and phosphatidylserines compared to healthy control hepatocytes. PHH cultured in a fatty acid-enriched environment demonstrated an increase in total lipid abundance, however, changes were limited to glycerolipids; in contrast to NASH hepatocytes, increases in the abundance of phospholipids were not observed.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Cultured Cells

DISEASE(S): Nash

SUBMITTER: Thomas Kralj

PROVIDER: ST002057 | MetabolomicsWorkbench | Wed Dec 08 00:00:00 GMT 2021

REPOSITORIES: MetabolomicsWorkbench

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Project description:The mechanisms underlying the progression of non-alcoholic steatohepatitis (NASH) are not completely elucidated. In this study we have integrated gene expression profiling of liver biopsies of NASH patients with translational studies in a mouse model of steatohepatitis and with pharmacological interventions in isolated hepatocytes to identify a novel mechanism implicated in the pathogenesis of NASH. By using high-density oligonucleotide microarray analysis we identified a significant enrichment of known genes involved in the multi-step catalysis of long chain polyunsaturated fatty acids, including delta-5 and 6 desaturases. A combined inhibitor of delta-5 and delta-6 desaturases significantly reduced intracellular lipid accumulation and inflammatory gene expression in isolated hepatocytes. Gas chromatography analysis revealed impaired delta-5 desaturase activity toward the omega-3 pathway in livers from mice with high-fat diet (HFD)-induced NASH. Consistently, restoration of omega-3 index in transgenic fat-1 mice expressing an omega-3 desaturase, which allows the endogenous conversion of omega-6 into omega-3 fatty acids, produced a significant reduction in hepatic insulin resistance, hepatic steatosis, macrophage infiltration and necroinflammatory liver injury, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were comparable to those obtained in a group of mice receiving a HFD supplemented with EPA/DHA. Of interest, hepatocytes from fat-1 mice or supplemented with EPA exhibited synergistic anti-steatotic and anti-inflammatory actions with the delta-5/ delta-6 inhibitor. Conclusion: These findings indicate that both endogenous and exogenous restoration of the hepatic balance between omega-6 and omega-3 fatty acids and/or modulation of desaturase activities exert preventive actions in NASH. The complete database comprised the expression measurements of 18185 genes for liver sample groups: 8 non-alcoholic steatohepatitis (NASH ) and 7 control samples. This dataset is part of the TransQST collection.

Dataset Information

Distinct Human Hepatocyte Lipidomics Profiles for Nonalcoholic Steatohepatitis and In Vitro-Induced Steatosis

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