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

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.

Non-alcoholic fatty liver disease:Immunological mechanisms and current treatments

Non-alcoholic fatty liver disease(NAFLD)causes significant global disease burden and is a leading cause of mortality.NAFLD induces a myriad of aberrant changes in hepatocytes at both the cellular and molecular level.Although the disease spectrum of NAFLD is widely recognised,the precise triggers for disease progression are still to be fully elucidated.Furthermore,the propagation to cirrhosis is poorly understood.Whilst some progress in terms of treatment options have been explored,an incomplete understanding of the hepatic cellular and molecular alterations limits their clinical utility.We have therefore reviewed some of the key pathways responsible for the pathogenesis of NAFLD such as innate and adaptative immunity,lipotoxicity and fibrogenesis,and highlighted current trials and treatment options for NAFLD patients.

Alcoholic liver disease:Current insights into cellular mechanisms

Alcoholic liver disease(ALD)due to chronic alcohol consumption is a significant global disease burden and a leading cause of mortality.Alcohol abuse induces a myriad of aberrant changes in hepatocytes at both the cellular and molecular level.Although the disease spectrum of ALD is widely recognized,the precise triggers for disease progression are still to be fully elucidated.Oxidative stress,mitochondrial dysfunction,gut dysbiosis and altered immune system response plays an important role in disease pathogenesis,triggering the activation of inflammatory pathways and apoptosis.Despite many recent clinical studies treatment options for ALD are limited,especially at the alcoholic hepatitis stage.We have therefore reviewed some of the key pathways involved in the pathogenesis of ALD and highlighted current trials for treating patients.