Reduced dietary omega-6 to omega-3 fatty acid ratio and 12/15-lipoxygenase deficiency are protective against chronic high fat diet-induced steatohepatitis

LAZIC M; INZAUGARAT ME; POVERO D; ZHAO IC; CHEN M; NALBANLDIAN N; MILLER Y; CHERÑAVSKY AC.; FELDSTEIN A; SEARS DD

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2014 vol. 9

1932-6203

Obesity is associated with metabolic perturbations including liver and adipose tissue inflammation, insulin resistance, and type 2 diabetes. Omega-6 fatty acids (ω6) promote and omega-3 fatty acids (ω3) reduce inflammation as they can be metabolizedto pro- and anti-inflammatory eicosanoids, respectively. 12/15-lipoxygenase (12/15-LO) enzymatically produces some of these metabolites and is induced by high fat (HF) diet. We investigated the effects of altering dietary ω6/ω3 ratio and 12/15-LO deficiency on HF diet-induced tissue inflammation and insulin resistance.We examined how these conditions affectcirculating concentrations of oxidized metabolites of ω6arachidonic and linoleic acids and innate and adaptive immune system activity in the liver.For 15 weeks, wild-type (WT) mice were fed either a soybean oil-enriched HF diet with high dietary ω6/ω3 ratio (11:1, HF¬H), similar to Western-style diet, or a fat Kcal-matched, fish oil-enriched HFdiet with a low dietary ω6/ω3 ratio of 2.7:1 (HFL). Importantly, the total saturated, monounsaturated and polyunsaturated fat content was matched in the two HF diets, which is unlike most published fish oil studies in mice. Despite modestly increased food intake, WT mice fed HFL wereprotected from HFH-diet induced steatohepatitis, evidenced by decreased hepatic expression of pro-inflammatory genes, reduced lymphocyte homing in the liver, and reduced deposition of hepatic triglyceride.Furthermore, oxidized metabolites of ω6arachidonic acid were decreased in the plasma of WT HFL compared to WT HFH-fed mice. 12/15-LO knockout (KO) mice were also protected from HFH-induced fatty liver, liver inflammation and lymphocyte homing. We show that activation of the hepatic lymphocyte homing response is elevated in patients with nonalcoholic fatty liver disease. 12/15-LO KO mice were protected from HFH-induced insulin resistance but reducing dietary ω6/ω3 ratio in WT mice did not ameliorate insulin resistance or adipose tissue inflammation. In conclusion, lowering dietary ω6/ω3 ratio in HF diet significantly reducessteatohepatitis.