Linoleic Acid‐Derived Oxylipins Differentiate Early Stage of 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 heavy drinking individuals and to test the hypothesis that elevated plasma LA-derived lipoxins may facilitate progression from mild to more severe ALD. We postulated that the specific changes in LA-derived lipid mediators could effectively differentiate mild ALD from early stage of AH. Analysis of plasma LA-derived metabolites was performed on 66 heavy drinking individuals and 29 socially drinking but otherwise healthy volunteers. Based on plasma 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, MELD < 20). The standard blood biochemical parameters, including total bilirubin (T-Bili), albumin, as well as plasma pro-inflammatory cytokines were evaluated. LOX-derived LA metabolites, 13-HODE and 13-oxoODE, were markedly elevated only in mAH patients. The CYP450-derived LA epoxides, 9,10-EpOME and 12,13-EpOME were decreased in all patients regardless of the presence or the absence of liver injury. LA-derived diols, 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. Significantly elevated T-bili and decreased albumin levels were observed in mAH patients compared to all other groups. Plasma TNF-α was significantly elevated in all groups of heavy drinking individuals compared to controls, while IL-1β was significantly higher only in mAH patients as compared to all other groups. Multiple regression analysis revealed that 13-HODE and 12,13-EpOME (elevated and decreased, respectively) in combination with elevated IL-1β can effectively predict altered liver function in mAH patients as defined by elevated T-Bili levels. In conclusion, the current study provides evidence that specific changes in LA-metabolites in heavy drinking individuals can distinguish individuals with mAH from those with mild ALD.