High omega arachidonic acid/docosahexaenoic acid ratio induces mitochondrial dysfunction and altered lipid metabolism in human hepatoma cells

查看全文 作　　者：Reem [1,2]Ghazali;Kosha J [3]Mehta;SW Annie [1,4]Bligh;Ihab [1]Tewfik;Dahn [5]Clemens;Vinood B [1]Patel

机构地区：[1]School of Life Sciences,University of Westminster,London W1W 6UW,United Kingdom;[2]Clinical Biochemistry Department,Faculty of medicine,King Abdulaziz University,Jeddah 21589,Saudi Arabia;[3]Centre for Education,Faculty of Life Sciences and Medicine,King's College London SE11UL,United Kingdom;[4]Caritas Institute of Higher Education,Hong Kong 999077,China;[5]Nebraska and Western Iowa Veterans Administration Medical Center and Department of Internal Medicine,University of Nebraska Medical Center,Omaha,NE 68198,United States

出　　处：《World Journal of Hepatology》索引2020年第12卷第3期,共15页

摘　　要：BACKGROUND Non-alcoholic fatty liver disease(NAFLD) is a common cause of liver disease worldwide and is a growing epidemic. A high ratio of omega-6 fatty acids to omega-3 fatty acids in the diet has been implicated in the development of NAFLD. However, the inflicted cellular pathology remains unknown. A high ratio may promote lipogenic pathways and contribute to reactive oxygen species(ROS)-mediated damage, perhaps leading to mitochondrial dysfunction.Therefore, these parameters were investigated to understand their contribution to NAFLD development.AIM To examine the effect of increasing ratios of omega-6:3 fatty acids on mitochondrial function and lipid metabolism mediators.METHODS Hep G2-derived VL-17 A cells were treated with normal(1:1, 4:1) and high(15:1,25:1) ratios of omega-6: omega-3 fatty acids [arachidonic acid(AA):docosahexaenoic acid(DHA)] at various time points. Mitochondrial activity and function were examined via MTT assay and Seahorse XF24 analyzer, respectively.Triglyceride accumulation was determined by using Enzy Chrom? and levels of ROS were measured by fluorescence intensity. Protein expression of the mediators of lipogenic, lipolytic and endocannabinoid pathways was assessed by Western blotting.RESULTS High AA:DHA ratio decreased mitochondrial activity(P < 0.01;up to 80%) and promoted intracellular triglyceride accumulation(P < 0.05;40%-70%).Mechanistically, it altered the mediators of lipid metabolism;increased the expression of stearoyl-Co A desaturase(P < 0.05;22%-35%), decreased the expression of peroxisome proliferator-activated receptor-alpha(P < 0.05;30%-40%) and increased the expression of cannabinoid receptor 1(P < 0.05;31%).Furthermore, the high ratio increased ROS production(P < 0.01;74%-115%) and reduced mitochondrial respiratory functions such as basal and maximal respiration, ATP production, spare respiratory capacity and proton leak(P < 0.01;35%-68%).CONCLUSION High AA:DHA ratio induced triglyceride accumulation, increased oxidative stress and disrupted mitochondrial functions. Stimulation of lipogenic and steroidal transcription factors may partly mediate these effects and contribute to NAFLD development. 关键词：Non-alcoholic FATTY liver disease LIPOGENESIS OMEGA FATTY ACIDS Mitochondrial dysfunction Reactive oxygen species Oxidative stress

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High omega arachidonic acid/docosahexaenoic acid ratio induces mitochondrial dysfunction and altered lipid metabolism in human hepatoma cells

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