title: NAADP-mediated Ca2+signaling promotes autophagy and protects against LPS-induced liver injury.
abstract: LPS has been shown to induce hepatocyte autophagy, but little is known about how LPS is able to do this during acute toxic liver injury. Our aim was to determine the existence of any selective Ca2+signaling coupling to hepatocyte autophagy in response to LPS. LPS increased the autophagic process in hepatocytes, and CD38 knockdown prevented this response. Ned19, a specific inhibitor for nicotinic acid adenine dinucleotide phosphate (NAADP), prevented LPS-mediated Ca2+signaling and autophagosome formation in hepatocytes. CD38 overexpression protected the liver from LPS/d-galactosamine (GalN)-induced injury, and NAADP administration promoted autophagosome formation and protected hepatocytes from injury induced by LPS/GalN. Autophagy was promoted by the up-regulation of autophagy-related gene expressionviaNAADP-mediated Ca2+signaling in response to LPS. However, CD38-knockout mice displayed down-regulation in hepatocyte gene expression. Ned19 also inhibited the NAADP-stimulated induction of gene expression by inhibiting the LPS-induced nuclear translocation of transcription factor EB (TFEB). Hepatocyte autophagy protects against LPS-induced liver injuryviathe CD38/NAADP/Ca2+/TFEB pathway. The role of NAADP-mediated Ca2+signaling in the autophagic process will help elucidate the complexities of autophagy regulation, which is essential toward the discovery of new therapeutic tools against acute liver injury.-Rah, S.-Y., Lee, Y.-H., Kim, U.-H. NAADP-mediated Ca2+signaling promotes autophagy and protects against LPS-induced liver injury.
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School.|National Creative Research Laboratory for Ca Signaling Network, Chonbuk National University Medical School.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Rah
authors.affiliation: Department of Oral Anatomy, School of Dentistry, Chonbuk National University, Jeonju, South Korea.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School; uhkim@chonbuk.ac.kr.|National Creative Research Laboratory for Ca Signaling Network, Chonbuk National University Medical School.|Institute of Cardiovascular Research, Chonbuk National University, Jeonju, South Korea.
authors.forename: Uh-Hyun
authors.initials: UH
authors.lastname: Kim
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002243:Carbolines / Q000494:pharmacology; D016923:Cell Death; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009249:NADP / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology
chemical_list: D002243:Carbolines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C000614918:Ned-19 compound; D010879:Piperazines; D009249:NADP; C024376:NAADP; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium
keywords: CD38; TFEB; calcium; gene expression; hepatocytes