Linoleic Acid‐Derived Oxylipins Differentiate Early Stage Alcoholic Hepatitis From Mild Alcohol‐Associated Liver Injury

Abstract

Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. Alcohol-associated hepatitis (AH) is an acute and often severe form of ALD with substantial morbidity and mortality. The mechanisms and mediators of ALD progression and severity are not well understood, and effective therapeutic options are limited. Various bioactive lipid mediators have recently emerged as important factors in ALD pathogenesis. The current study aimed to examine alterations in linoleic acid (LA)-derived lipid metabolites in the plasma of individuals who are heavy drinkers and to evaluate associations between these molecules and markers of liver injury and systemic inflammation. Analysis of plasma LA-derived metabolites was performed on 66 individuals who were heavy drinkers and 29 socially drinking but otherwise healthy volunteers. Based on plasma alanine aminotransferase (ALT) levels, 15 patients had no liver injury (ALT ≤ 40 U/L), 33 patients had mild liver injury (ALT > 40 U/L), and 18 were diagnosed with moderate AH (mAH) (Model for End-Stage Liver Disease score <20). Lipoxygenasederived LA metabolites (13-hydroxy-octadecadienoic acid [13-HODE] and 13-oxo-octadecadienoic acid) were markedly elevated only in patients with mAH. The cytochrome P450-derived LA epoxides 9,10-epoxy-octadecenoic acid (9,10-EpOME) and 12,13-EpOME were decreased in all patients regardless of the presence or absence of liver injury. LA-derived diols 9,10-dihydroxy-octadecenoic acid (9,10-DiHOME) and 12,13-DiHOME as well as the corresponding diol/epoxide ratio were elevated in the mAH group, specifically compared to patients with mild liver injury. We found that 13-HODE and 12,13-EpOME (elevated and decreased, respectively) in combination with elevated interleukin-1β as independent predictors can effectively predict altered liver function as defined by elevated bilirubin levels. Conclusion: Specific changes in LA metabolites in individuals who are heavy drinkers can distinguish individuals with mAH from those with mild ALD. (Hepatology Communications 2021;0:1-14). L ong-term heavy alcohol consumption results in the development of a spectrum of liver disorders ranging from steatosis to steatohepatitis with varying degrees of fibrosis and cirrhosis, collectively known as alcohol-associated liver disease (ALD). ALD affects millions of patients worldwide

Hepatic Protein and Phosphoprotein Signatures of Alcohol-Associated Cirrhosis and Hepatitis

“…13 A lipidomics approach was recently used to discriminate ALD stages based on changes in plasma levels of lipid species (eg, elevated levels of 13hydroxyoctadecadienoic acid, 9,10-dihydroxyoctadecenoate, and 12,13-dihydroxyoctadecenoate in moderate AH versus heavy drinkers with mild ALD). 14 Because the gut-liver axis plays an important role in ALD, metagenomics has been applied to elucidate microbial/bacterial changes contributing to the disease development/progression (eg, cytolysinpositive Enterococcus faecalis was identified as a pathogenic bacterium in clinical AH and successfully targeted in experimental AH 15 ). Certainly, omic studies have been invaluable for identifying biomarkers, novel mechanisms, and therapeutic targets for AC and AH.…”

The mitochondrial biliverdin exporter ABCB10 in hepatocytes mitigates neutrophilic inflammation in alcoholic hepatitis

“…Therefore, it is feasible that decreased ABCB10 function resulted in the release of a higher quantity of irreversibly oxidized lipids and protein-adducts from hepatocytes to activate the initiation of NET formation in infiltrated neutrophils. Consistent with this interpretation, high oxylipins content in liver correlates with the severity of AH [ [25] , [26] , [27] ] and are potent inducers of NET formation as well [ [28] , [29] , [30] ]. We are currently setting up an in vitro system to determine which of these two possibilities can explain how increased ABCB10 function in hepatocytes mitigates NET formation in neutrophils in livers with AH.…”

Identification of genes regulated by lipids from seaweed Susabinori (Pyropia yezoensis) involved in the improvement of hepatic steatosis: Insights from RNA-Seq analysis in obese db/db mice

“…Notably, the overexpression of CYP2J2 in FHD-mice not only elicited reduced inflammatory responses but also exhibited a significantly decreased in plasma triglyceride levels and liver lipid accumulation [ 27 ]. Furthermore, CYP2C-derived EpOMEs, EEQs, and EDPs are also known as important epoxides which reduce inflammation and autophagy in liver [ 28 , 29 ]. In fact, our research has revealed that SNL-fed db / db mice exhibited a significant decrease in the levels of hepatic triglyceride and the expression of inflammatory marker gene monocyte chemotactic protein 1 ( Mcp1 ), also known as Ccl2 , which is one of the 18 SNL-dependent down-regulated genes [ 7 ].…”