TY - JOUR
T1 - Brown fat activation mitigates alcohol-induced liver steatosis and injury in mice
AU - Shen, Hong
AU - Jiang, Lin
AU - Lin, Jiandie D.
AU - Bishr Omary, M.
AU - Rui, Liangyou
N1 - Funding Information:
We thank Yan Liu, Lei Yin, and Jun Wu for assistance and discussion. This study was supported by grants R01 DK091591, R01 DK094014 and R21 AA025945 (to LR); R01 DK102456 (to JDL); and R01 DK47918 (to MBO) from the NIH. This work utilized the cores supported by the Michigan Diabetes Research and Training Center (NIH DK20572), the University of Michigan’s Cancer Center (NIH CA46592), the University of Michigan Nathan Shock Center (NIH P30AG013283), and the University of Michigan Center for Gastrointestinal Research (NIH DK34933).
Publisher Copyright:
Copyright: © 2019, American Society for Clinical Investigation.
PY - 2019/6/3
Y1 - 2019/6/3
N2 - Chronic alcohol consumption causes liver injury, inflammation, and fibrosis, thereby increasing morbidity and mortality. Paradoxically, modest drinking is believed to confer metabolic improvement, but the underlying mechanism remains elusive. Here, we have identified a hepatoprotective brain/brown adipose tissue (BAT)/liver axis. Alcohol consumption or direct alcohol administration into the brain stimulated hypothalamic neural circuits and sympathetic nerves innervating BAT and dramatically increased BAT uncoupling protein 1 (Ucp1) expression and activity in a BAT-sympathetic nerve-dependent manner. BAT and beige fat oxidized fatty acids to fuel Ucp1-mediated thermogenesis, thereby inhibiting lipid trafficking into the liver. BAT also secreted several adipokines, including adiponectin, which suppressed hepatocyte injury and death. Genetic deletion of Ucp1 profoundly augmented alcohol-induced liver steatosis, injury, inflammation, and fibrosis in male and female mice. Conversely, activation of BAT and beige fat through cold exposure suppressed alcoholic liver disease development. Our results unravel an unrecognized brain alcohol-sensing/sympathetic nerve/BAT/liver axis that counteracts liver steatosis and injury.
AB - Chronic alcohol consumption causes liver injury, inflammation, and fibrosis, thereby increasing morbidity and mortality. Paradoxically, modest drinking is believed to confer metabolic improvement, but the underlying mechanism remains elusive. Here, we have identified a hepatoprotective brain/brown adipose tissue (BAT)/liver axis. Alcohol consumption or direct alcohol administration into the brain stimulated hypothalamic neural circuits and sympathetic nerves innervating BAT and dramatically increased BAT uncoupling protein 1 (Ucp1) expression and activity in a BAT-sympathetic nerve-dependent manner. BAT and beige fat oxidized fatty acids to fuel Ucp1-mediated thermogenesis, thereby inhibiting lipid trafficking into the liver. BAT also secreted several adipokines, including adiponectin, which suppressed hepatocyte injury and death. Genetic deletion of Ucp1 profoundly augmented alcohol-induced liver steatosis, injury, inflammation, and fibrosis in male and female mice. Conversely, activation of BAT and beige fat through cold exposure suppressed alcoholic liver disease development. Our results unravel an unrecognized brain alcohol-sensing/sympathetic nerve/BAT/liver axis that counteracts liver steatosis and injury.
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U2 - 10.1172/JCI124376
DO - 10.1172/JCI124376
M3 - Article
C2 - 30888335
AN - SCOPUS:85063280033
SN - 0021-9738
VL - 129
SP - 2305
EP - 2317
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -