Time course of western diet (WD) induced nonalcoholic steatohepatitis (NASH) in female and male Ldlr-/- mice.

Nonalcoholic fatty liver disease (NAFLD) is a global health problem. Identification of factors contributing to the onset and progression of NAFLD have the potential to direct novel strategies to combat NAFLD. We examined the time course of western diet (WD)-induced NAFLD and its progression to nonalcoholic steatohepatitis (NASH) in age-matched female and male Ldlr-/- mice, with time-points at 1, 4, 8, 20 and 40 weeks on the WD. Controls included Ldlr-/- mice maintained on a purified low-fat diet (LFD) for 1 and 40 weeks. The approach included quantitation of anthropometric, plasma and liver markers of disease, plus hepatic histology, lipids, oxylipins, gene expression and selected metabolites. One week of feeding the WD caused a significant reduction in hepatic essential fatty acids (EFAs: 18:2, ω6, 18:3, ω3) which preceded the decline in many C20-22 ω3 and ω6 polyunsaturated fatty acids (PUFA) and PUFA-derived oxylipins after 4 weeks on the WD. In addition, expression of hepatic inflammation markers (CD40, CD44, Mcp1, Nlrp3, TLR2, TLR4, Trem2) increased significantly in both female & male mice after one week on the WD. These markers continued to increase over the 40-week WD feeding study. WD effects on hepatic EFA and inflammation preceded all significant WD-induced changes in body weight, insulin resistance (HOMA-IR), oxidative stress status (GSH/GSSG ratio) and histological and gene expression markers of macrosteatosis, extracellular matrix remodeling and fibrosis. Our findings establish that feeding Ldlr-/- mice the WD rapidly lowered hepatic EFAs and induced key inflammatory markers linked to NASH. Since EFAs have an established role in inflammation and hepatic inflammation plays a major role in NASH, we suggest that early clinical assessment of EFA status and correcting EFA deficiencies may be useful in reducing NASH severity.

Spooner MH ，Garcia-Jaramillo M ，Apperson KD ，Löhr CV ，Jump DB ... -  《PLoS One》

Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible?

Lytle KA ，Jump DB 《PLoS One》

Lipidomic and transcriptomic analysis of western diet-induced nonalcoholic steatohepatitis (NASH) in female Ldlr -/- mice.

Garcia-Jaramillo M ，Spooner MH ，Löhr CV ，Wong CP ，Zhang W ，Jump DB ... -  《PLoS One》

A Lipidomic Analysis of Docosahexaenoic Acid (22:6, ω3) Mediated Attenuation of Western Diet Induced Nonalcoholic Steatohepatitis in Male Ldlr (-/-) Mice.

García-Jaramillo M ，Lytle KA ，Spooner MH ，Jump DB ... -  《Metabolites》

Docosahexaenoic acid blocks progression of western diet-induced nonalcoholic steatohepatitis in obese Ldlr-/- mice.

Lytle KA ，Wong CP ，Jump DB 《PLoS One》