Gene

Alcohol

Biology

Transgene

Liver disease

Steatosis

Steatohepatitis

Endocrinology

Fibrosis

Cirrhosis

Genetically modified mouse

Fatty acid

Biochemistry

Polyunsaturated fatty acid

Fatty liver

Physiology

Alcoholic liver disease

Inflammation

Internal medicine

Medicine

Chemistry

Gastroenterology

Disease

The FASEB Journal

Background/Objectives Alcohol‐induced liver disease (ALD) leads to significant morbidity and mortality and creates an enormous burden on the health care system. There are no effective treatment strategies for any stage of this disease, which range from steatosis, steatohepatitis, fibrosis, to the most severe stage, cirrhosis. Most chronic drinkers will develop early stages of ALD, but only a fraction will proceed to more advanced, life‐threatening stages. Therefore, beyond alcohol, other factors must contribute to ALD progression. The role of diet in ALD has been a focus of numerous preclinical studies. We and others have found that a diet with high levels of ω‐6 polyunsaturated fatty acids (PUFAs) exacerbates ALD in rodents. This effect may be due to elevated levels of pro‐inflammatory metabolites of ω‐6 PUFAs. Additionally, the large amount of ω‐6 PUFAs leads to a suboptimal ratio of ω‐6 to ω‐3 PUFAs. Hominids evolved in a dietary landscape that provided ω‐6:ω‐3 PUFAs ratio &lt;2:1, whereas modern diets can reach levels as high as 40:1. ω‐3 PUFAs have been proposed to have beneficial effects due to their metabolism to resolvins, maresins, and protectins, which promote the resolution phase of inflammation. In the current study we sought to determine if lowering the endogenous ω‐6:ω‐3 ratio attenuates experimental ALD and to identify hepatic gene expression changes underlying this effect. Methods To determine the impact of lowering the ω‐6:ω‐3 ratio, we used a transgenic mouse line ( fat‐1, provided by Dr. J. X. Kang) that directly desaturates ω‐6 ω‐3 PUFAs and therefore lowers the ω‐6:ω‐3 ratio in the absence of dietary modification. Male WT and fat‐1 +/ − mice were given an all liquid diet that contained increasing concentrations of EtOH over the course of 3 weeks, up to a final concentration of 6%. To simulate the severity of ALD in humans, LPS was administered to mice 24h before euthanasia (5 mg/kg, i.p.). Liver injury was assessed by plasma ALT activity and histopathology. Liver RNA was extracted and analyzed by RNA sequencing. Results Following EtOH‐LPS treatment, fat1 +/ − mice had significantly decreased liver damage compared to WT littermates as determined by lower plasma ALT activity (73±16 vs. 400±95 U/L, P &lt;0.05), reduced apoptosis, and neutrophil infiltration. RNA‐Seq analysis identified 73 genes with differential expression between the WT‐EtOH‐LPS and fat1 +/ − ‐EtOH‐LPS groups. Among these genes, 10 belonged to cytochrome p450s, many of which are involved in arachidonate and linoleate metabolism (known to generate pro‐inflammatory bioactive metabolites). Several genes in the ubiquitination/proteasomal degradation pathway, as well as number of growth and differentiation factors were also differentially expressed. Conclusions Results from this study demonstrated that fat1 +/ − mice have decreased EtOH‐induced liver damage, demonstrating the potential viability of using w3 PUFAs to treat ALD. Further studies examining the differential regulation of metabolic pathways as a potential targets of drug therapy are warranted. Support or Funding Information Supported by grants from NIH and Veterans Administration This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Hepatic Gene Expression Changes in a Mouse Model of Alcoholic Liver Disease: Effect of the w‐6:w‐3 Polyunsaturated Fatty Acid Ratio