title: TGR5 signaling reduces neuroinflammation during hepatic encephalopathy.
abstract: Hepatic encephalopathy (HE) is a serious neurological complication of acute and chronic liver failure. Expression of the neurosteroid/bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) has been demonstrated in the brain and is thought to be neuroprotective. However, it is unknown how TGR5 signaling can influence the progression and associated neuroinflammation of HE. HE was induced in C57Bl/6 mice via intraperitoneal injection of azoxymethane (AOM) and tissue was collected throughout disease progression. TGR5 expression was elevated in the frontal cortex following AOM injection in mice. The cellular localization of TGR5 was found in both neurons and microglia in the cortex of C57Bl/6 mice. Central infusion of the TGR5 agonist, betulinic acid, prior to AOM injection delayed neurological decline, increased cortical cyclic adenosine monophosphate concentrations, reduced microglia activation and proliferation, and reduced proinflammatory cytokine production. Betulinic acid treatment in vitro reduced the neuronal expression of chemokine ligand 2, a chemokine previously demonstrated to contribute to HE pathogenesis. Lastly, treatment of the microglia cell line EOC-20 with conditioned media from betulinic acid-treated primary neurons decreased phagocytic activity and cytokine production. Together, these data identify that activation of TGR5, which is up-regulated during HE, alleviates neuroinflammation and improves outcomes of AOM-treated mice through neuron and microglia paracrine signaling.
authors.affiliation: Central Texas Veterans Healthcare System, Temple, Texas, USA.|Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: McMillin
authors.affiliation: Central Texas Veterans Healthcare System, Temple, Texas, USA.|Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Frampton
authors.affiliation: Department of Surgery, Texas A&M Health Science Center and Baylor Scott & White Health, College of Medicine, Temple, Texas, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Tobin
authors.affiliation: Department of Surgery, Texas A&M Health Science Center and Baylor Scott & White Health, College of Medicine, Temple, Texas, USA.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Dusio
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Smith
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA.
authors.forename: Hope
authors.initials: H
authors.lastname: Shin
authors.affiliation: Department of Surgery, Texas A&M Health Science Center and Baylor Scott & White Health, College of Medicine, Temple, Texas, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Newell-Rogers
authors.affiliation: Central Texas Veterans Healthcare System, Temple, Texas, USA.|Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grant
authors.affiliation: Central Texas Veterans Healthcare System, Temple, Texas, USA.|Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA.|Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006501:Hepatic Encephalopathy / Q000378:metabolism* / Q000517:prevention & control*; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053978:Pentacyclic Triterpenes; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014315:Triterpenes / Q000008:administration & dosage; D000094062:Betulinic Acid
chemical_list: C513561:Gpbar1 protein, mouse; D053978:Pentacyclic Triterpenes; D043562:Receptors, G-Protein-Coupled; D014315:Triterpenes; D000094062:Betulinic Acid
keywords: GPBAR-1; IBA-1; acute liver failure; azoxymethane; betulinic acid; microglia