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Beneficial effects of an endogenous enrichment in n3‐PUFAs on Wnt signaling are associated with attenuation of alcohol‐mediated liver disease in mice
Author(s) -
Warner Dennis R.,
Warner Jeffrey B.,
Hardesty Josiah E.,
Song Ying L.,
Chen ChiYu,
Chen Zoe,
Kang Jing X.,
McClain Craig J.,
Kirpich Irina A.
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202001202r
Subject(s) - wnt signaling pathway , fatty liver , axin2 , steatohepatitis , hepatocyte , endocrinology , polyunsaturated fatty acid , chemistry , steatosis , medicine , signal transduction , biology , cancer research , biochemistry , fatty acid , disease , in vitro
Alcohol‐associated liver disease (ALD) is a major human health issue for which there are limited treatment options. Experimental evidence suggests that nutrition plays an important role in ALD pathogenesis, and specific dietary fatty acids, for example, n6 or n3‐PUFAs, may exacerbate or attenuate ALD, respectively. The purpose of the current study was to determine whether the beneficial effects of n3‐PUFA enrichment in ALD were mediated, in part, by improvement in Wnt signaling. Wild‐type (WT) and fat‐1 transgenic mice (that endogenously convert n6‐PUFAs to n3) were fed ethanol (EtOH) for 6 weeks followed by a single LPS challenge. fat‐1 mice had less severe liver damage than WT littermates as evidenced by reduced plasma alanine aminotransferase, hepatic steatosis, liver tissue neutrophil infiltration, and pro‐inflammatory cytokine expression. WT mice had a greater downregulation of Axin2 , a key gene in the Wnt pathway, than fat‐1 mice in response to EtOH and LPS. Further, there were significant differences between WT and fat‐1 EtOH+LPS‐challenged mice in the expression of five additional genes linked to the Wnt signaling pathway, including Apc, Fosl1/Fra‐1, Mapk8/Jnk‐1, Porcn , and Nkd1 . Compared to WT, primary hepatocytes isolated from fat‐1 mice exhibited more effective Wnt signaling and were more resistant to EtOH‐, palmitic acid‐, or TNFα‐induced cell death. Further, we demonstrated that the n3‐PUFA‐derived lipid mediators, resolvins D1 and E1, can regulate hepatocyte expression of several Wnt‐related genes that were differentially expressed between WT and fat‐1 mice. These data demonstrate a novel mechanism by which n3‐PUFAs can ameliorate ALD.