Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY/ABSTRACT Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, claiming more than 3 million deaths globally (Liangpunsakul, Haber et al. 2016). The pathogenesis of alcohol-induced liver injury is characterized by hepatic steatosis, inflammation, and fibrosis, which can progress to cirrhosis and liver cancer (Gao and Bataller 2011, Williams, Manley et al. 2014, Nagy, Ding et al. 2016). Despite major progress in understanding mechanisms for ALD, no successful treatment is available. Cells can adapt and protect themselves in response to stress by activating cellular protective mechanisms such as autophagy, a cellular catabolic process that degrades cellular proteins and subcellular organelles. Additional protective mechanisms that are activated due to stress, such as the unfolded protein (UPR) and integrated stress (ISR) responses aid in eliminating stress affecting the endoplasmic reticulum (ER). Autophagy and ER stress are tightly integrated as ER stress can activate autophagy to regulate ER homeostasis and relieve ER stress. Our lab has been studying autophagy in ALD and our previous work shows that alcohol consumption impairs hepatic autophagy resulting in ALD. We demonstrated that alcohol activates mechanistic target of rapamycin complex 1 (mTORC1) and impairs transcription factor EB (TFEB)-mediated lysosomal biogenesis and autophagy. Aging is a well-known risk factor associated with ALD. Alcohol consumption has increased in age groups older than 60 leading to an increased susceptibility to developing ALD in these groups. There is a lack of research that focuses on alcohol consumption in older adults as the mechanisms by which alcohol and aging cooperatively contribute to the pathogenesis of ALD in this age group remain incompletely understood. It is known that autophagy and lysosomal functions decline with aging as well. Increased stress and impairment to the ER are associated with chronic alcohol consumption as well as aging. My preliminary data showed impaired hepatic TFEB function in aged mice, which is associated with altered mitochondria metabolic changes, hepatic inflammation, and activated ER stress response systems in alcohol-fed aged mouse livers. However, how autophagy and ER stress as well as aging regulate liver metabolism and contribute to ALD in aging population is unknown. The overall goal of this project is to identify and understand the mechanisms in which aging and alcohol consumption cooperatively contribute to the overall decline in liver function and the subsequent development of ALD.
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