Alterations in hepatic albumin phosphorylation in patients with alcohol‐associated hepatitis and cirrhosis

Abstract

BackgroundAlcohol‐associated liver disease (ALD) encompasses a range of disease states including alcohol‐associated hepatitis (AH) and cirrhosis (AC), two severe clinical manifestations with high mortality due to compromised liver function. One key function of the liver is to synthesize and secrete albumin (ALBU), which plays a critical role in maintaining overall homeostasis. Hypoalbuminemia is a common feature of AH and AC; however, the contributing mechanisms are not established. Recently, S82‐ALBU phosphorylation via FA20A/C was shown to be required for hepatocellular release of ALBU. In this study, we hypothesized that hypoalbuminemia in AH and AC may occur in part due to hepatocellular retention secondary to compromised ALBU phosphorylation.MethodsProteomic and phosphoproteomic analyses were conducted using LC/MS/MS on liver biopsy samples from AH patients (n=34), AC patients (n=10), and non‐ALD controls (n=10). Further, AH patients were stratified by MELD score (Model for End‐stage Liver Disease) as follows: AH1 (MELD 17‐20), AH2 (21‐25), AH3 (26‐29), and AH4 (30‐37). Significantly changed proteins were correlated with MELD and compared between non‐surviving and surviving AH patients. One‐way ANOVA was used for comparisons between three groups (parametric), unpaired Student’s t‐test was used for two groups (parametric), and Pearson’s correlation was used for regression analysis. A p<0.05 was considered statistically significant.ResultsExpression of hepatic ALBU was elevated in AH and AC patients relative to non‐ALD controls and was positively associated with MELD in AH patients. Among AH severity groups, liver ALBU was further elevated from AH3 to AH4. We further observed that pS82‐ALBU, and its allosteric regulator FA20A (molecules involved in ALBU release), were reduced in AH and AC relative to non‐ALD controls. This would suggest that one mechanism of increased expression of hepatic ALBU may be due to inhibition of its release. These results for AH were confirmed in an independent cohort.ConclusionThis study demonstrated that hepatic ALBU levels are elevated in AH and AC, likely due to the loss of pS82 phosphorylation by FA20A/C, compromising hepatocellular ALBU release. Altered ALBU phosphorylation and subsequent release could be a key pathogenic mechanism of hypoalbuminemia in AH and AC. Further studies are warranted to test this hypothesis.