Jun Xu1, Keane K Y Lai2, Alla Verlinsky2, Aurelia Lugea3, Samuel W French4, Marcus P Cooper5, Cheng Ji6, Hidekazu Tsukamoto3. 1. Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine of the University of Southern California, USA. Electronic address: junx@usc.edu. 2. Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine of the University of Southern California, USA. 3. Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine of the University of Southern California, USA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA. 4. Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine of the University of Southern California, USA; Harbor-UCLA Medical Center, Torrance, CA, USA. 5. Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, MA, USA. 6. Department of Medicine, Keck School of Medicine of the University of Southern California, USA.
Abstract
BACKGROUND & AIMS: Mechanisms underlying synergistic liver injury caused by alcohol and obesity are not clear. We have produced a mouse model of synergistic steatohepatitis by recapitulating the natural history of the synergism seen in patients for mechanistic studies. METHODS: Moderate obesity was induced in mice by 170% overnutrition in calories using intragastric overfeeding of high fat diet. Alcohol (low or high dose) was then co-administrated to determine its effects. RESULTS: Moderate obesity plus alcohol intake causes synergistic steatohepatitis in an alcohol dose-dependent manner. A heightened synergism is observed when a high alcohol dose (32g/kg/d) is used, resulting in plasma ALT reaching 392±28U/L, severe steatohepatitis with pericellular fibrosis, marked M1 macrophage activation, a 40-fold induction of iNos, and intensified nitrosative stress in the liver. Hepatic expression of genes for mitochondrial biogenesis and metabolism are significantly downregulated, and hepatic ATP level is decreased. Synergistic ER stress evident by elevated XBP-1, GRP78 and CHOP is accompanied by hyperhomocysteinemia. Despite increased caspase 3/7 cleavage, their activities are decreased in a redox-dependent manner. Neither increased PARP cleavage nor TUNEL positive hepatocytes are found, suggesting a shift of apoptosis to necrosis. Surprisingly, the synergism mice have increased plasma adiponectin and hepatic p-AMPK, but adiponectin resistance is shown downstream of p-AMPK. CONCLUSIONS: Nitrosative stress mediated by M1 macrophage activation, adiponectin resistance, and accentuated ER and mitochondrial stress underlie potential mechanisms for synergistic steatohepatitis caused by moderate obesity and alcohol.
BACKGROUND & AIMS: Mechanisms underlying synergistic liver injury caused by alcohol and obesity are not clear. We have produced a mouse model of synergistic steatohepatitis by recapitulating the natural history of the synergism seen in patients for mechanistic studies. METHODS: Moderate obesity was induced in mice by 170% overnutrition in calories using intragastric overfeeding of high fat diet. Alcohol (low or high dose) was then co-administrated to determine its effects. RESULTS: Moderate obesity plus alcohol intake causes synergistic steatohepatitis in an alcohol dose-dependent manner. A heightened synergism is observed when a high alcohol dose (32g/kg/d) is used, resulting in plasma ALT reaching 392±28U/L, severe steatohepatitis with pericellular fibrosis, marked M1 macrophage activation, a 40-fold induction of iNos, and intensified nitrosative stress in the liver. Hepatic expression of genes for mitochondrial biogenesis and metabolism are significantly downregulated, and hepatic ATP level is decreased. Synergistic ER stress evident by elevated XBP-1, GRP78 and CHOP is accompanied by hyperhomocysteinemia. Despite increased caspase 3/7 cleavage, their activities are decreased in a redox-dependent manner. Neither increased PARP cleavage nor TUNEL positive hepatocytes are found, suggesting a shift of apoptosis to necrosis. Surprisingly, the synergism mice have increased plasma adiponectin and hepatic p-AMPK, but adiponectin resistance is shown downstream of p-AMPK. CONCLUSIONS: Nitrosative stress mediated by M1 macrophage activation, adiponectin resistance, and accentuated ER and mitochondrial stress underlie potential mechanisms for synergistic steatohepatitis caused by moderate obesity and alcohol.
Authors: Mercedes Vázquez-Chantada; Usue Ariz; Marta Varela-Rey; Nieves Embade; Nuria Martínez-Lopez; David Fernández-Ramos; Laura Gómez-Santos; Santiago Lamas; Shelly C Lu; M Luz Martínez-Chantar; José M Mato Journal: Hepatology Date: 2009-02 Impact factor: 17.425
Authors: Marta Varela-Rey; Nieves Embade; Usue Ariz; Shelly C Lu; José M Mato; M Luz Martínez-Chantar Journal: Int J Biochem Cell Biol Date: 2008-11-05 Impact factor: 5.085
Authors: Sudheer K Mantena; Denty Paul Vaughn; Kelly K Andringa; Heather B Eccleston; Adrienne L King; Gary A Abrams; Jeannette E Doeller; David W Kraus; Victor M Darley-Usmar; Shannon M Bailey Journal: Biochem J Date: 2009-01-01 Impact factor: 3.857