Fat-1 Transgenic Mice With Augmented n3-Polyunsaturated Fatty Acids Are Protected From Liver Injury Caused by Acute-On-Chronic Ethanol Administration

Abstract

Alcohol-associated liver disease (ALD) is the leading cause of liver disease worldwide, and alcohol-associated hepatitis (AH), a severe form of ALD, is a major contributor to the mortality and morbidity due to ALD. Many factors modulate susceptibility to ALD development and progression, including nutritional factors such as dietary fatty acids. Recent work from our group and others showed that modulation of dietary or endogenous levels of n6-and n3-polyunsaturated fatty acids (PUFAs) can exacerbate or attenuate experimental ALD, respectively. In the current study, we interrogated the effects of endogenous n3-PUFA enrichment in a mouse model which recapitulates features of early human AH using transgenic fat-1 mice which endogenously convert n6-PUFAs to n3-PUFAs. Male wild type (WT) and fat-1 littermates were provided an ethanol (EtOH, 5% v/v)-containing liquid diet for 10 days, then administered a binge of EtOH (5 g/kg) by oral gavage on the 11th day, 9 h prior to sacrifice. In WT mice, EtOH treatment resulted in liver injury as determined by significantly elevated plasma ALT levels, whereas in fat-1 mice, EtOH caused no increase in this biomarker. Compared to their pair-fed controls, a significant EtOH-mediated increase in liver neutrophil infiltration was observed also in WT, but not fat-1 mice. The hepatic expression of several cytokines and chemokines, including Pai-1, was significantly lower in fat-1 vs WT EtOH-challenged mice. Cultured bone marrow-derived macrophages isolated from fat-1 mice expressed less Pai-1 and Cxcl2 (a canonical neutrophil chemoattractant) mRNA compared to WT when stimulated with lipopolysaccharide. Further, we observed decreased pro-inflammatory M1 liver tissue-resident macrophages (Kupffer cells, KCs), as well as increased liver T regulatory cells in fat-1 vs WT EtOH-fed mice. Taken together, our data demonstrated protective effects of endogenous n3-PUFA enrichment on liver injury caused by an acute-on-chronic EtOH exposure, a paradigm which recapitulates human AH, suggesting that n3-PUFAs may be a viable nutritional adjuvant therapy for this disease.

Essential lipid autacoids rewire mitochondrial energy efficiency in metabolic dysfunction‐associated fatty liver disease

“…The results of the current study also provide a mechanistic basis by which fat-1 mice are resistant to obesity-induced hepatic steatosis, insulin resistance, inflammation in insulin-sensitive tissues (white adipose tissue [WAT] and liver), and liver fibrosis. [18,19] Our findings might also explain why animals endogenously enriched with omega-3-PUFAs are protected against alcohol-induced liver injury, [40] a condition characterized by widespread mitochondrial damage. [41] Our study also provides some mechanistic insights beyond the liver cells as to why omega-3-PUFA-enriched animals have a reduced risk for noncommunicable diseases including metabolic disease, colon inflammation-triggered injury, pancreatitis, acute lung injury, inflammatory burden during preterm birth, vascular inflammation, and neuroinflammatory injury among others in which loss of mitochondria function is common.…”

Fpr2−/− Mice Developed Exacerbated Alcohol-Associated Liver Disease

“…BMDMs and hepatic non-parenchymal cells were isolated from WT and Fpr2 −/− mice (n = 3 per genotype) as previously described [22]. Cells were then immunostained with PE-F4/80, FITC-Ly6C, and PerCy5.5-Cd11b (Invitrogen, Waltham, MA, USA) to identify the monocyte (F4/80 lo , Ly6C hi , Cd11b + ) and MoMF populations (F4/80 hi , Ly6C lo , Cd11b + ) by flow cytometry.…”

The Role of Gut Bacteria and Fungi in Alcohol-Associated Liver Disease

“…Saturated long-chain fatty acids are decreased in ethanol intragastric mice, and maintaining the levels of saturated fatty acids in the intestine promote commensal Lactobacillus growth and stabilize gut barrier ( 30 ). The n3-polyunsaturated fatty acids (PUFAs) can attenuate experimental ALD through decreasing neutrophil chemoattract ( 61 ).…”