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Roles of NR and GPCR network focusing on autophagy in liver diseases
講演者:Prof. Sang Geon KIM 所属:College of Pharmacy, Dongguk University-Seoul

開催日:2023-04-14 10:00

終了日:2023-04-14 11:30





日 時:令和5年4月14日(金)10001130

開催場所:病院地区キャンパス 薬学部附設システム創薬リサーチセンター グリーンファルマ研究所402


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タイトル:Roles of NR and GPCR network focusing on autophagy in liver diseases

演 者:Prof. Sang Geon KIM (College of Pharmacy, Dongguk University-Seoul)

要 旨:

Autophagy is a catabolic process in which autophagosomes are formed de novo to engulf cytosolic contents such as damaged organelles, lipids, and proteins. Autophagy is essential for the maintenance of intracellular homeostasis, and thus autophagy dysfunction is associated with various liver diseases. Autophagy is suppressed in liver diseases caused by excessive high fat intake, which leads to excessive liver fat accumulation and accelerated disease progression. In fatty liver disease, ATG4B and Rab8b regulate different stages of the autophagy flux. ATG4B is involved in the initiation phase, processing LC3, whereas Rab8b causes fusion of autophagosome with the lysosome in the maturation phase. Previsously, we have shown that LXRα induces the accumulation of lipids through induction of a number of lipogenic genes such as SREBP1 and SCD1. In addition, chronic alcohol intake promotes fat accumulation in hepatocytes through changes in fat metabolism. Especially, accumulating evidence suggests that autophagy plays a role in the progression of ALD. Chronic alcohol abuse suppresses autophagy, resulting in excessive lipid accumulation and damaged mitochondria. Therefore, enhancing autophagy can attenuate ALD progression. In this study, we found that repetitive alcohol exposure caused AhR overexpression and activation, dysregulating autophagy, as verified by hepatocyte-specific Ahr knockout models. In RNA-seq and metabolomic analyses, alcohol treatment led to the inhibition of AhR-dependent autophagy. Autophagy dysregulation was mediated with a change in AMPKα dephosphorylation. In lipidomics and mitochondrial assays, hepatocyte-specific AhR ablation diminished triglyceride and glycerophospholipid accumulation by facilitating autophagy-dependent fuel burning and oxygen consumption. Our results identify a new metabotropic mechanism by which AhR regulates autophagy and lipid catabolism during alcoholic liver disease exacerbation.



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