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The stabilization of new lipid mediators derived from omega-3 fatty acids reduces the liver inflammation caused by obesity

The non-alcoholic steatohepatitis (NASH), also known as fatty liver disease, is a disease associated with obesity characterized by an accumulation of fat in liver cells accompanied by an inflammatory process that causes lesions similar to those suffered by people who consume alcohol in toxic amounts. A study led by Dr. Joan Clària, researcher at the IDIBAPS group Pathophysiology and treatment of ascites and altered renal function in liver cirrhosis, and consultant of the Biochemistry and Molecular Genetics Department at Hospital Clínic, demonstrates, for the first time, that the inhibition of the enzyme responsible for the degradation of lipid mediators derived from omega-3 can modulate inflammation associated with fat accumulation in the liver. In addition, these compounds, called epoxides, make liver cells able to eliminate fat through autophagy. This study, published in the journal Proceedings of the National Academy of Sciences (PNAS), has been carried out in collaboration with researchers from the University of California (Davis).  The first author of the work is Cristina López-Vicario, predoctoral researcher of the IDIBAPS group.

Omega-3 are essential polyunsaturated fatty acids that are present in cell membranes which are converted in the liver to epoxides by the presence of metabolic enzymes. These epoxides have anti-inflammatory properties, can reduce oxidative stress and have the ability to increase autophagy, or, in other words, they promote the elimination of what is harmful to the cell. The only drawback is that these epoxides are unstable molecules with a lifetime of a few seconds as they are inactivated by an enzyme, the soluble epoxide hydrolase (SEH). Until now, several studies have shown the benefits of inhibiting this enzyme in the field of hypertension. In this study, published in PNAS, researchers have focused on demonstrating that this inhibition may also play a role in NASH, since in this disease the enzyme is present in large quantities in the liver.

Thus, researchers studied the effect of a drug developed by Professor Bruce Hammock at the University of California (Davis) to inhibit the enzyme sEH specifically. Obese mice genetically modified to have tissues enriched omega-3 (to generate large quantities of epoxides) were used to test the drug efficacy. Researcher form IDIBAPS found that inhibition of the enzyme that degrades these epoxides reduces the liver inflammation associated with fat accumulation and increases autophagy by the hepatic cells. Moreover, they found that this effect also occurs in obese adipose tissue.

Inhibitors of sEH are suggested as a promising therapeutic strategy to prevent and counteract the consequences of obesity. Based on the significant results obtained in this work new studies will be launched to test the efficacy of the drug in patients with obesity and fatty liver disease.

Article reference:

Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: Role for omega-3 epoxides.

López-Vicario C, Alcaraz-Quiles J, García-Alonso V, Rius B, Hwang SH, Titos E, Lopategi A, Hammock BD, Arroyo V, Clària J.

Proc Natl Acad Sci U S A. 2014 Dec 30. pii: 201422590. [Epub ahead of print] PMID: 25550510 [PubMed - as supplied by publisher]