title: Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model.
abstract: Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in α-smooth muscle actin (α-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and α-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis.
authors.affiliation: Division of Interventional Radiology, Russell H. Morgan Department of Radiology & Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Swathi
authors.initials: S
authors.lastname: Karthikeyan
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Potter
authors.affiliation: Division of Interventional Radiology, Russell H. Morgan Department of Radiology & Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: jeff.geschwind@yale.edu.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Geschwind
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Surojit
authors.initials: S
authors.lastname: Sur
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Hamilton
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Mezey
authors.affiliation: Division of Interventional Radiology, Russell H. Morgan Department of Radiology & Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: gshanmu1@jhmi.edu.
authors.forename: Shanmugasundaram
authors.initials: S
authors.lastname: Ganapathy-Kanniappan
mesh_terms: D000818:Animals; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects*; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011773:Pyruvates / Q000008:administration & dosage*
chemical_list: C543636:3-bromo-2-oxopropionic acid; D011773:Pyruvates
keywords: 3-Bromopyruvate; Hepatic stellate cells; Liver fibrosis; Metabolism