|NEESON, CAMERON - Tufts University|
|WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
Submitted to: JSM Gastroenterology and Hepatology
Publication Type: Review Article
Publication Acceptance Date: 3/29/2023
Publication Date: 3/30/2023
Citation: Neeson, C., Wang, X. 2023. Implication of SIRT1 on Development of Nonalcoholic Fatty Liver Disease and Impact of Carotenoid Intervention. JSM Gastroenterology and Hepatology. 10(1):1114.
Technical Abstract: Cellular senescence is a biological process that drives age-related disease development, including age-related nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Although the growth arrest associated with senescence can prevent malignant transformation, senescence also alters the cellular microenvironment through a senescence-associated secretory phenotype (SASP), resulting in increased inflammation, disease progression, and tumorigenesis over time. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, controls many signaling pathways involved in senescence, aging, and tumorigenesis. The loss of SIRT1 activity has been shown to promote NAFLD by mobilizing free fatty acids to the liver from adipose tissue in mice. The contribution of hepatocyte senescence to NAFLD and HCC has been reported; however, whether diminished SIRT1 activity drives adipocyte senescence, facilitates lipolysis, and promotes NAFLD/HCC is currently unclear. Studies have shown that feeding tomato powder (a source of lycopene) or lycopenoids (lycopene and its metabolite, lycopenoic acid) increases SIRT1 levels in the liver and adipose tissue, preventing NAFLD and HCC. It is unknown whether loss of SIRT1 activity promotes senescence-driven lipolysis/SASP in liver and adipose tissue or if carotenoid consumption limits this senescence, thereby preventing NAFLD and HCC. This review proposes that 1) lack of SIRT1 activity induces senescence and increases lipolysis/SASP in hepatocyte senescence and adipose tissue, the latter increasing movement of fatty acids to the liver and promoting hepatocyte senescence, NAFLD and HCC; and 2) dietary carotenoids increase SIRT1 activity and regulate hepatocyte senescence, adipocyte senescence, and lipolysis, and thus prevent NAFLD and HCC development.