Ethanol and unsaturated dietary fat induce unique patterns of hepatic ω-6 and ω-3 PUFA oxylipins in a mouse model of alcoholic liver disease

作者：Warner, Dennis R.; Liu, Huilin; Dastidar, Shubha Ghosh; Warner, Jeffrey B.; Prodhan, Md Aminul Islam; Yin, Xinmin; Zhang, Xiang; Feldstein, Ariel E.; Gao, Bin; Prough, Russell A.; McClain, Craig J.; Kirpich, Irina A.^*

来源：PLos One, 2018, 13(9): e0204119.

DOI：10.1371/journal.pone.0204119

• SOLUBLE EPOXIDE HYDROLASE
• ENDOPLASMIC-RETICULUM STRESS
• OXIDIZED LIPID PRODUCTS
• NONALCOHOLIC STEATOHEPATITIS
• ADIPOSE-TISSUE
• MACROPHAGE ACTIVATION
• INSULIN-RESISTANCE
• ACID-METABOLISM
• AMNIOTIC-FLUID
• SATURATED FAT

Alcoholic liver disease (ALD), a significant health problem, progresses through the course of several pathologies including steatosis, steatohepatitis, fibrosis, and cirrhosis. There are no effective FDA-approved medications to prevent or treat any stages of ALD, and the mechanisms involved in ALD pathogenesis are not well understood. Bioactive lipid metabolites play a crucial role in numerous pathological conditions, as well as in the induction and resolution of inflammation. Herein, a hepatic lipidomic analysis was performed on a mouse model of ALD with the objective of identifying novel metabolic pathways and lipid mediators associated with alcoholic steatohepatitis, which might be potential novel biomarkers and therapeutic targets for the disease. We found that ethanol and dietary unsaturated, but not saturated, fat caused elevated plasma ALT levels, hepatic steatosis and inflammation. These pathologies were associated with increased levels of bioactive lipid metabolites generally involved in pro-inflammatory responses, including 13-hydroxy-octadecadienoic acid, 9,10- and 12,13-dihydroxy-octadecenoic acids, 5-, 8-, 9-, 11-, 15-hydroxy-eicosatetraenoic acids, and 8,9- and 11,12-dihydroxy-eicosatrienoic acids, in parallel with an increase in proresolving mediators, such as lipoxin A4, 18-hydroxy-eicosapentaenoic acid, and 10S,17S-dihydroxy-docosahexaenoic acid. Elucidation of alterations in these lipid metabolites may shed new light into the molecular mechanisms underlying ALD development/progression, and be potential novel therapeutic targets.

• 单位
  吉林大学