title: The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca(2+) signalling in steatotic hepatocytes.
abstract: The release of Ca(2+) from the endoplasmic reticulum (ER) and subsequent replenishment of ER Ca(2+) by Ca(2+) entry through store-operated Ca(2+) channels (SOCE) play critical roles in the regulation of liver metabolism by adrenaline, glucagon and other hormones. Both ER Ca(2+) release and Ca(2+) entry are severely inhibited in steatotic hepatocytes. Exendin-4, a slowly-metabolised glucagon-like peptide-1 (GLP-1) analogue, is known to reduce liver glucose output and liver lipid, but the mechanisms involved are not well understood. The aim of this study was to determine whether exendin-4 alters intracellular Ca(2+) homeostasis in steatotic hepatocytes, and to evaluate the mechanisms involved. Exendin-4 completely reversed lipid-induced inhibition of SOCE in steatotic liver cells, but did not reverse lipid-induced inhibition of ER Ca(2+) release. The action of exendin-4 on Ca(2+) entry was rapid in onset and was mimicked by GLP-1 or dibutyryl cyclic AMP. In steatotic liver cells, exendin-4 caused a rapid decrease in lipid (half time 6.5min), inhibited the accumulation of lipid in liver cells incubated in the presence of palmitate plus the SOCE inhibitor BTP-2, and enhanced the formation of cyclic AMP. Hormone-stimulated accumulation of extracellular glucose in glycogen replete steatotic liver cells was inhibited compared to that in non-steatotic cells, and this effect of lipid was reversed by exendin-4. It is concluded that, in steatotic hepatocytes, exendin-4 reverses the lipid-induced inhibition of SOCE leading to restoration of hormone-regulated cytoplasmic Ca(2+) signalling. The mechanism may involve GLP-1 receptors, cyclic AMP, lipolysis, decreased diacylglycerol and decreased activity of protein kinase C.
authors.affiliation: Department of Medical Biochemistry and Centre for Neuroscience, School of Medicine, Flinders University, Adelaide, South Australia 5001, Australia.
authors.forename: Eunüs S
authors.initials: ES
authors.lastname: Ali
authors.affiliation: Department of Medical Biochemistry and Centre for Neuroscience, School of Medicine, Flinders University, Adelaide, South Australia 5001, Australia.
authors.forename: Jin
authors.initials: J
authors.lastname: Hua
authors.affiliation: Molecular Regulation Laboratory, Centre for Cancer Biology, Division of Health Sciences, University of South Australia, Adelaide, South Australia, 5001, Australia.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Wilson
authors.affiliation: Medical Biochemistry, SA Pathology, Finders Medical Centre, Bedford Park, South Australia 5042, Australia.
authors.forename: George A
authors.initials: GA
authors.lastname: Tallis
authors.affiliation: School of Medicine, The University of Adelaide, and South Australian Health and Medical Research Institute, Adelaide, South Australia 5005, Australia.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Zhou
authors.affiliation: School of Medicine, The University of Adelaide, and South Australian Health and Medical Research Institute, Adelaide, South Australia 5005, Australia.
authors.forename: Grigori Y
authors.initials: GY
authors.lastname: Rychkov
authors.affiliation: Department of Medical Biochemistry and Centre for Neuroscience, School of Medicine, Flinders University, Adelaide, South Australia 5001, Australia. Electronic address: greg.barritt@flinders.edu.au.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Barritt
mesh_terms: D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D000077270:Exenatide; D005234:Fatty Liver / Q000473:pathology*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006728:Hormones / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D011924:Rats, Zucker; D014688:Venoms / Q000494:pharmacology*
chemical_list: D006728:Hormones; D010455:Peptides; D014688:Venoms; D019308:Palmitic Acid; D003994:Bucladesine; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D000242:Cyclic AMP; D002118:Calcium
keywords: Cyclic AMP; Exendin-4; GLP-1; Intracellular Ca(2+); Liver; Steatosis; Store operated Ca(2+) entry