Integrated Multi-Omics Analysis Reveals Glucose Metabolic Reprogramming and Identifies a Novel Hexokinase in Alcoholic Hepatitis

Purpose: We recently demonstrated that alcoholic hepatitis (AH) is characterized by de-differentiation of hepatocytes and loss of mature functions. Glucose metabolism is tighly regulated in healthy hepatocytes. We hypothesize that AH may lead to metabolic reprogramming of the liver, including dysregulation of glucose metabolism. Methods: We performed integrated metabolomic and transcriptomic analyses of liver tissue from patients with AH (n=13), alcoholic cirrhosis (n=10) or normal liver tissue from hepatic resection (n=16). Focused analyses of chromatin immunoprecipitation coupled to DNA sequencing (ChIP-seq) was performed. Functional in vitro studies were performed in primary rat and human hepatocytes and HepG2 cells. Results: Patients with AH exhibited specific changes in the levels of intermediates of glycolysis/gluconeogenesis, the TCA cycle, and monosaccharide and disaccharide metabolism. Integrative analysis of the transcriptome and metabolome revealed the utilization of alternate energetic pathways, metabolite sinks and bottlenecks, and improper glucose storage in AH patients. Among genes involved in glucose metabolism, hexokinase domain containing 1 (HKDC1) was identified as the most up-regulated kinase in AH patients. Histone active promoter and enhancer markers were increased in HKDC1 genomic region. High HKDC1 levels were associated with the development of acute kidney injury and decreased survival. Increased HKDC1 activity contributed to the accumulation of G6P and glycogen in primary rat hepatocytes. Conclusion: Altered metabolite levels and mRNA expression of metabolic enzymes suggest the existence of profound reprogramming of glucose metabolism in AH. Increased HKDC1 expression may contribute to dysregulated glucose metabolism and may serve as a novel biomarker and therapeutic target for AH. Overall design: Transcriptome analysis of liver biopsies from 28 patients with alcoholic hepatitis (10 samples), cirrhosis (6 samples) or healthy livers (12 samples).