Alcoholic liver disease (ALD) remains an important health problem in the United States. It ranks among the major causes of morbidity and mortality in the world, and affects millions of patients worldwide each year. The disease process is characterized by early steatosis, steatohepatitis, with some individuals ultimately progressing to fibrosis/cirrhosis and liver failure. Currently, there is no accepted therapy available to halt or reverse this process in humans. Adipose tissue dysfunction plays a critical role in the pathogenesis of ALD; however, the exact mechanisms underlying the detrimental effect of alcohol on adipocyte function remain elusive. In mammals, adipose tissues comprise white adipose tissue (WAT) and brown adipose tissue (BAT), which is further categorized into ?classical? BAT and ?inducible? beige fat. The adipocytes in beige fat are Ucp1-expressing thermogenic adipocytes and can be induced to manifest the phenotypes of classical brown adipocytes via a process called ?browning?. Sympathetic nervous system (SNS) is the primary initiator of both lipolysis and browning process through releasing norepinephrine (NE) at target adipose tissues. Physiologically, a tightly-regulated ?coupling? between lipolytic and thermogenic machinery activation must be maintained to assure that most fatty acids released from adipose tissue by lipolysis can be ultimately utilized for thermogenesis process/heat production. The promotive effect of chronic alcohol consumption on lipolysis activation has been well- documented, in contrast, its effect on adipose tissue browning/thermogenic process, as well as its potential involvement in the pathogenesis of ALD development, remain unknown. Furthermore, although the profound effect of alcohol on central nervous system (CNS) has been widely reported, whether and how CNS contributes to these processes remain ambiguous. The data obtained recently in my laboratory revealed that ALD development was associated with adipose tissue cAMP/PKA pathway activation. Nevertheless, chronic alcohol exposure inhibited adipose tissue ?browning?, implying a ?dissociation? between the two physiologically coupled processes in response to increased SNS tone in response to alcohol drinking. Based on our Preliminary Studies, we hypothesize that chronic alcohol consumption activates SNS, however, it ?dissociates? the coupling between lipolysis and browning/thermogenesis in adipose tissues, leading to uncontrolled FFAs release and resultant fatty liver and liver damage. This hypothesis will be tested in the following Specific Aims:
AIM 1 : To determine the critical role of SNS activation in adipose tissue lipolysis and liver pathologies in response to chronic alcohol exposure;
AIM 2 : To determine the pathological role of impaired browning/thermogenesis process in ALD and mechanism(s) underlying alcohol-triggered uncoupling between lipolysis and browning/thermogenesis;
and AIM 3 : To elucidate the mechanism(s) underlying alcohol-induced sympathetic activation.

Public Health Relevance

Liver damage induced by chronic alcohol drinking (alcoholic liver disease, ALD) remains an important health problem in the United States and ranks among the major causes of morbidity and mortality in the world, and affects millions of patients worldwide each year, with no accepted therapy available to halt or reverse this process in humans. The recent preliminary studies in our laboratory demonstrated that chronic alcohol exposure is associated with aberrant adipose tissue physiology. Our further investigations suggest that alcohol drinking dissociated the coupling between lipolysis and browning/thermogenesis of adipose tissue, which may play a pathological role in the development of ALD and represent an ideal therapeutic target for the clinical intervention. In this proposal, we will utilize state of the art approaches to test our hypotheses using both cell culture and animal models.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Radaeva, Svetlana
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University of Illinois at Chicago
Sch Allied Health Professions
United States
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