title: Metabolic reprogramming and cell fate regulation in alcoholic liver disease.
abstract: Alcoholic liver disease (ALD) should be defined as a life-style metabolic disease. Its pathogenesis is driven by altered cell fate of both parenchymal and non-parenchymal liver cell types, contributing to different pathologic spectra. A critical turning point in progression of ALD is chronic alcoholic steatohepatitis (ASH) or alcoholic neutrophilic hepatitis (AH), which markedly predisposes patients to most devastating ALD sequela, cirrhosis and liver cancer.
  
  
  RESULTS
  Our research identifies the pivotal roles of unique metabolic reprogramming in M1 activation of hepatic macrophages (HM) and myofibroblastic activation (MF) of hepatic stellate cells (HSC) in the genesis of inflammation and fibrosis, the two key histological features of chronic ASH and neutrophilic AH. For M1 HM activation, heightened proinflammatory iron redox signaling in endosomes or caveosomes results from altered iron metabolism and storage, promoting IKK/NF-kB activation via interactive activation of p21ras, TAK1, and PI3K. For MF cell fate regulation of HSC, activation of the morphogen Wnt pathway caused by the nuclear protein NECDIN or the single-pass trans-membrane protein DLK1, reprograms lipid metabolism via MeCP2-mediated epigenetic repression of the key HSC quiescence gene Ppar-γ.
  
  
  CONCLUSIONS
  The findings from these studies re-enforce the importance of metabolic reprogramming in cell fate regulation required for the pathogenesis of ALD.
authors: Southern California Research Center ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine of the University of Southern California, Greater Los Angeles VA Healthcare System, Los Angeles, CA, USA. Electronic address: htsukamo@med.usc.edu.
authors: Hidekazu
authors: H
authors: Tsukamoto
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology*; D008262:Macrophage Activation
keywords: Hepatic stellate cells; Iron; M1 macrophage activation; MeCP2; Morphogens; Wnt