Hepatic Steatosis and ER Stress-Inducible Transcription Factor CREBH

Summary

Principal Investigator: Kezhong Zhang
Abstract: DESCRIPTION (provided by applicant): Hepatic steatosis or fatty liver is considered the key metabolic precursor to non-alcoholic fatty liver disease (NAFLD), the major cause of liver-associated illness and death in the United States. Disease progression in NAFLD is currently thought to be triggered by an acute insult (the "second hit") that is imposed on hepatic steatosis (the "first hit"). However, a precise understanding of the molecular basis by which the "two hits" trigger the transition from reversible steatosis to NAFLD remains elusive. Previously, we revealed a novel liver- specific transcription factor CREBH (cyclic-AMP-response-element-binding protein H), which is activated by endoplasmic reticulum (ER) stress to mediate an acute-phase inflammatory response in the liver. Recently, we have accumulated strong preliminary evidence that CREBH plays a crucial role in regulating hepatic lipid homeostasis under metabolic stress conditions. Saturated fatty acids, inflammatory stimuli, or high-fat feeding can induce cleavage of CREBH in vitro or in vivo, leading to its activation. Deletion of CREBH in mice resulted in decreased expression of key lipogenic enzymes and reduced hepatic lipid accumulation in response to acute ER stress or atherogenic high-fat feeding. After the high-fat feeding for 6 months, CREBH null mice displayed significantly less hepatic steatosis and inflammation but greater insulin sensitivity and glucose tolerance, compared to the control mice. Furthermore, CREBH was found to activate expression of key lipogenic regulators, including CCAAT-enhancer-binding protein beta (C/EBP2) and peroxisome proliferator- activated receptor gamma (PPAR3), in liver hepatocytes under the metabolic stress. These observations lead to the central hypothesis of this proposal: metabolic stress, induced by excessive saturated fatty acids or pro- inflammatory cytokines, activates CREBH;activated CREBH then functions as a lipogenic transcriptional regulator to propagate hepatic steatosis and steatohepatitis. In this grant application, we will elucidate the pathophysiologic role and molecular mechanism of CREBH in regulating hepatic steatosis and the development of NAFLD. To achieve our research goal, we will pursue three complementary specific aims: (1) to delineate the regulatory mechanism by which metabolic factors, including saturated fatty acids and pro- inflammatory cytokines, activate CREBH;(2) to decipher the molecular basis of CREBH-mediated stress signaling in regulating hepatic lipid homeostasis;(3) to determine the role of CREBH in the transition of hepatic steatosis to steatohepatitis under the metabolic stress. This work represents a novel avenue to elucidate ER stress-associated mechanisms in hepatic steatosis and steatohepatitis that are currently poorly understood. Completion of the proposed studies will not only define the molecular basis by which a novel, stress-induced transcription factor regulates hepatic lipid metabolism, but will also be significant for designing new strategies for the prevention and treatment of human NAFLD and its associated metabolic syndromes. PUBLIC HEALTH RELEVANCE: Non-alcoholic fatty liver disease (NAFLD), the major cause of liver-associated illness and deaths, frequently precedes or co-exists with obesity, type II diabetes, and cardiovascular disease. This project will identify the regulatory mechanisms by which a novel stress-inducible transcription factor CREBH promotes fatty liver and progression of NAFLD under metabolic stress. Understanding the stress-induced molecular mechanisms in hepatic lipid accumulation and its associated pathogenesis is a key prerequisite for the development of new diagnostics and therapeutics targeting NAFLD.
Funding Period: 2011-01-01 - 2015-12-31
more information: NIH RePORT

Top Publications

  1. pmc Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice
    Chunbin Zhang
    Center for Molecular Medicine and Genetics, the Wayne State University School of Medicine, Detroit, MI 48201, USA
    Hepatology 55:1070-82. 2012
  2. pmc Pharmacologic ER stress induces non-alcoholic steatohepatitis in an animal model
    Jin Sook Lee
    Center for Molecular Medicine and Genetics, the Wayne State University School of Medicine, Detroit, MI 48201, USA
    Toxicol Lett 211:29-38. 2012
  3. pmc Endoplasmic reticulum factor ERLIN2 regulates cytosolic lipid content in cancer cells
    Guohui Wang
    Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Biochem J 446:415-25. 2012
  4. pmc Exposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model
    Ze Zheng
    Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
    J Hepatol 58:148-54. 2013
  5. pmc Exposure to fine airborne particulate matter induces macrophage infiltration, unfolded protein response, and lipid deposition in white adipose tissue
    Roberto Mendez
    Center for Molecular Medicine and Genetics, Wayne State University School of Medicine Detroit, MI 48201, USA
    Am J Transl Res 5:224-34. 2013
  6. pmc Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis
    Quan Qiu
    Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
    EMBO J 32:2477-90. 2013
  7. pmc The serine-threonine kinase inositol-requiring enzyme 1α (IRE1α) promotes IL-4 production in T helper cells
    KYEORDA L KEMP
    From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611
    J Biol Chem 288:33272-82. 2013
  8. pmc Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor α to regulate metabolic hormone FGF21
    Hyunbae Kim
    Center for Molecular Medicine and Genetics H K, R M, Z Z, J C, R Z, K Z, Department of Immunology and Microbiology K Z, the Wayne State University School of Medicine, Detroit, Michigan 48201 and Cardiovascular Center L C, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109
    Endocrinology 155:769-82. 2014

Research Grants

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013

Detail Information

Publications8

  1. pmc Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice
    Chunbin Zhang
    Center for Molecular Medicine and Genetics, the Wayne State University School of Medicine, Detroit, MI 48201, USA
    Hepatology 55:1070-82. 2012
    ..Supporting the role of CREBH in lipogenesis and lipolysis, forced expression of an activated form of CREBH protein in the liver significantly increases accumulation of hepatic lipids, but reduces plasma TG levels in mice...
  2. pmc Pharmacologic ER stress induces non-alcoholic steatohepatitis in an animal model
    Jin Sook Lee
    Center for Molecular Medicine and Genetics, the Wayne State University School of Medicine, Detroit, MI 48201, USA
    Toxicol Lett 211:29-38. 2012
    ..Our study not only confirmed that pharmacologic ER stress is a strong "hit" that triggers NASH, but also demonstrated crucial molecular links between ER stress, lipid metabolism, and inflammation in the liver in vivo...
  3. pmc Endoplasmic reticulum factor ERLIN2 regulates cytosolic lipid content in cancer cells
    Guohui Wang
    Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Biochem J 446:415-25. 2012
    ..The identification of ERLIN2 as a regulator of cytosolic lipid content in cancer cells has important implications for understanding the molecular basis of tumorigenesis and the treatment of cancer...
  4. pmc Exposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model
    Ze Zheng
    Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
    J Hepatol 58:148-54. 2013
    ..5 μm (PM(2.5)) to the development of metabolic diseases. In this study, we investigated the effect of PM(2.5) exposure on liver pathogenesis and the mechanism by which ambient PM(2.5) modulates hepatic pathways and glucose homeostasis...
  5. pmc Exposure to fine airborne particulate matter induces macrophage infiltration, unfolded protein response, and lipid deposition in white adipose tissue
    Roberto Mendez
    Center for Molecular Medicine and Genetics, Wayne State University School of Medicine Detroit, MI 48201, USA
    Am J Transl Res 5:224-34. 2013
    ..These results provide novel insights into PM2.5-triggered cell stress response in adipose tissue and increase our understanding of pathophysiological effects of particulate air pollution on the development of metabolic disorders...
  6. pmc Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis
    Quan Qiu
    Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
    EMBO J 32:2477-90. 2013
    ....
  7. pmc The serine-threonine kinase inositol-requiring enzyme 1α (IRE1α) promotes IL-4 production in T helper cells
    KYEORDA L KEMP
    From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611
    J Biol Chem 288:33272-82. 2013
    ..This study identifies a regulatory function for IRE1α in the promotion of IL-4 in T cells. ..
  8. pmc Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor α to regulate metabolic hormone FGF21
    Hyunbae Kim
    Center for Molecular Medicine and Genetics H K, R M, Z Z, J C, R Z, K Z, Department of Immunology and Microbiology K Z, the Wayne State University School of Medicine, Detroit, Michigan 48201 and Cardiovascular Center L C, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109
    Endocrinology 155:769-82. 2014
    ..The functional relationship between CREBH and PPARα in regulating FGF21 may represent an important transcriptional coactivation mechanism that orchestrates the processes of energy supply upon metabolic alteration. ..

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..