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Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression.

ABSTRACT: The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5?-cholestane-3?,5,6?-triol (triol) combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury.

SUBMITTER: Bellanti F

PROVIDER: S-EPMC5725223 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression.

Bellanti Francesco F Villani Rosanna R Tamborra Rosanna R Blonda Maria M Iannelli Giuseppina G di Bello Giorgia G Facciorusso Antonio A Poli Giuseppe G Iuliano Luigi L Avolio Carlo C Vendemiale Gianluigi G Serviddio Gaetano G

Redox biology 20171205

The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation ...[more]

PMID: 29220698

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Project description:Two major isoforms of human carboxylesterases (CEs) are found in metabolically active tissues, CES1 and CES2. These hydrolytic enzymes are involved in xenobiotic and endobiotic metabolism. CES1 is abundantly expressed in human liver and monocytes/macrophages, including the THP1 cell line; CES2 is expressed in liver but not in monocytes/macrophages. The cholesteryl ester hydrolysis activity in human macrophages has been attributed to CES1. Here, we report the direct inhibitory effects of several endogenous oxysterols and fatty acids on the CE activity of THP1 monocytes/macrophages and recombinant human CES1 and CES2. Using THP1 whole-cell lysates we found: (1) 27-hydroxycholesterol (27-HC) is a potent inhibitor of carboxylesterase activity (IC50=33 nM); (2) 24(S),25-epoxycholesterol had moderate inhibitory activity (IC(50)=8.1 microM); and (3) cholesterol, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 25-hydroxycholesterol each had little inhibitory activity. 27-HC was a partially noncompetitive inhibitor of recombinant CES1 (K(iapp)=10 nM) and impaired intracellular CES1 activity following treatment of intact THP1 cells. In contrast, recombinant CES2 activity was not inhibited by 27-HC, suggesting isoform-selective inhibition by 27-HC. Furthermore, unsaturated fatty acids were better inhibitors of CES1 activity than saturated fatty acids, while CES2 activity was unaffected by any fatty acid. Arachidonic acid (AA) was the most potent fatty acid inhibitor of recombinant CES1 and acted by a noncompetitive mechanism (K(iapp)=1.7 microM); when not complexed to albumin, exogenous AA penetrated intact THP1 cells and inhibited CES1. Inhibition results are discussed in light of recent structural models for CES1 that describe ligand binding sites separate from the active site. In addition, oxysterol-mediated inhibition of CES1 activity was demonstrated by pretreatment of human liver homogenates or intact THP1 cells with exogenous 27-HC, which resulted in significantly reduced hydrolysis of the pyrethroid insecticide bioresmethrin, a CES1-specific xenobiotic substrate. Collectively, these findings suggest that CE activity of recombinant CES1, cell lysates, and intact cells can be impaired by naturally occurring lipids, which may compromise the ability of CES1 to both detoxify environmental pollutants and metabolize endogenous compounds in vivo.

Project description:BackgroundNon-alcoholic fatty liver disease (NAFLD) is a wide spectrum condition characterized by excessive liver fat accumulation in people who do not abuse alcohol. There is no effective medical treatment for NAFLD; therefore, most important recommendations to reduce liver steatosis are diet and lifestyle, including proper physical activity. The aim of our study was to analyze the fatty acids and eicosanoids changes in the serum of patients who consumed high-fiber rolls for 8 weeks.Materials and methodsThe group of 28 Caucasian participants was randomly divided into two groups, those who received 24 g of fiber/day-from 2 buns of 12 g each (n = 14), and those who received 12 g of fiber/day-from 2 buns of 6 g (n = 14). At the beginning and on the last visit of the 8-week intervention, all patients underwent NAFLD evaluation, biochemical parameter measurements, and fatty acids and eicosanoids evaluation.ResultsPatients who received 12 g of fiber had significantly reduced liver steatosis and body mass index. In the group who received 24 g of fiber/day, we observed a trend to liver steatosis reduction (p = 0.07) and significant decrease in aspartate aminotransferase (p = 0.03) and total cholesterol (p = 0.03). All changes in fatty acid and eicosanoids profile were similar. Fatty acids analysis revealed that extra fiber intake was associated with a significant increase in monounsaturated fatty acids and decrease in saturated fatty acids. Moreover, both groups showed increased concentration of gamma linoleic acid and docosahexaenoic acid. We also observed reduction in prostaglandin E2.ConclusionsOur study revealed that a high amount of fiber in the diet is associated with a reduction in fatty liver, although this effect was more pronounced in patients in the lower fiber group. However, regardless of the amount of fiber consumed, we observed significant changes in the profile of FAs, which may reflect the positive changes in the lipids liver metabolism. Regardless of the amount of fiber consumed, patients decreased the amount of PGE2, which may indicate the lack of disease progression associated with the development of inflammation.

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Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression.

Publications

Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression.

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