Published online Mar 27, 2020. doi: 10.4254/wjh.v12.i3.84
Peer-review started: July 16, 2019
First decision: November 2, 2019
Revised: December 24, 2019
Accepted: January 14, 2020
Article in press: January 14, 2020
Published online: March 27, 2020
Fatty liver disease is due to the consumption of excess dietary calories as well as a disruption in lipid metabolism and leads to the condition non-alcoholic fatty liver disease (NAFLD). The prevalence of NAFLD in most Western societies ranges from 20%-50%. Whilst the mechanisms for NAFLD development are complex, NAFLD patients show higher levels of omega-6 fatty acids than omega 3 fatty acids. Omega 6 fatty acids are known to be damaging to the liver causing toxicity, but their precise role in the pathology of NAFLD is not understood. This was an important question since NAFLD is a major public health problem and alternative interventions are required.
The main treatment options for NAFLD are dietary and lifestyle changes. We therefore addressed the question of how diet increases the risk of NAFLD, specifically the role of omega 6 fatty acids in relation to omega 3 fatty acids. Since this is a modifiable risk factor it is important to understand how high levels of omega 6 fatty acids can damage the liver and whether omega 3 fatty acids can minimise/reduce this damage. This will lead to improved understanding of NAFLD development and new therapeutic treatment options.
This research study aimed to understand the role of high omega 6:omega 3 ratios in a hepatic cell line model of NAFLD, thus allowing its contribution to lipotoxicity, oxidative stress and mitochondrial function to be investigated. These findings may help explain the progression from fatty liver to the inflammatory state, non-alcoholic steatohepatitis.
Human hepatoma cells, named VL-17A were treated with a range of high and normal ratios of omega-6: omega-3 fatty acids [arachidonic acid (AA): docosahexaenoic acid (DHA)]. These novel experiments examined the effect of these ratios on mitochondrial function, oxidative stress and viability. Changes in lipid accumulation combined with the expression of relevant lipogenic proteins was also assessed.
High omega-6:omega-3 (AA:DHA) ratio altered several processes in VL-17A cells. It reduced mitochondrial activity indicating lipotoxicity, increased triglyceride accumulation, elevated reactive oxygen species levels and interrupted several mitochondrial functions. Moreover, our study provided mechanistic data as to which of these detrimental effects may be mediated under high omega-6: omega-3 conditions and contribute to NAFLD development. Specifically, these include increased expression of stearoyl-CoA desaturase and decreased expression of peroxisome proliferator-activated receptor alpha. Also, elevation in cannabinoid receptor CB1 expression was observed that has been positively associated with fatty liver development. The present study clearly demonstrates the potential long-term consequences of high omega-6:3 ratios in NAFLD development.
The conclusions from this study strongly suggest that high omega 6:omega 3 ratios are detrimental to liver function, promoting an oxidant environment combined with higher amounts of lipid accumulation. These features are the hallmark of NAFLD indicating that altered omega 6:3 fatty acid ratios play an important role in NAFLD development and progression. Therefore, the original hypothesis was confirmed which can form the basis for further mechanistic studies examining other omega 6 fatty acids in NAFLD pathogenesis. The study also supports various studies where clinical interventions using omega 3 fatty acids have been utilised for NAFLD treatment.
Whilst further work is required, when investigating patients with NAFLD, measurement of circulating omega fatty acids should be considered. This may lead to the possibility of treating patients with omega 3 fatty acids. Other interventions that ameliorate oxidative stress and which improve mitochondrial function also require future research as this may lead to the reversal of NAFLD.