title: Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure.
abstract: Hepatic encephalopathy is a serious neurological complication of liver failure. Serum bile acids are elevated after liver damage and may disrupt the blood-brain barrier and enter the brain. Our aim was to assess the role of serum bile acids in the neurological complications after acute liver failure. C57Bl/6 or cytochrome p450 7A1 knockout (Cyp7A1(-/-)) mice were fed a control, cholestyramine-containing, or bile acid-containing diet before azoxymethane (AOM)-induced acute liver failure. In parallel, mice were given an intracerebroventricular infusion of farnesoid X receptor (FXR) Vivo-morpholino before AOM injection. Liver damage, neurological decline, and molecular analyses of bile acid signaling were performed. Total bile acid levels were increased in the cortex of AOM-treated mice. Reducing serum bile acids via cholestyramine feeding or using Cyp7A1(-/-) mice reduced bile acid levels and delayed AOM-induced neurological decline, whereas cholic acid or deoxycholic acid feeding worsened AOM-induced neurological decline. The expression of bile acid signaling machinery apical sodium-dependent bile acid transporter, FXR, and small heterodimer partner increased in the frontal cortex, and blocking FXR signaling delayed AOM-induced neurological decline. In conclusion, circulating bile acids may play a pathological role during hepatic encephalopathy, although precisely how they dysregulate normal brain function is unknown. Strategies to minimize serum bile acid concentrations may reduce the severity of neurological complications associated with liver failure.
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Healthcare System, Temple, Texas.
authors.forename: Matthew
authors.initials: M
authors.lastname: McMillin
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Healthcare System, Temple, Texas.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Frampton
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina.
authors.forename: Matthew
authors.initials: M
authors.lastname: Quinn
authors.affiliation: Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas.
authors.forename: Samir
authors.initials: S
authors.lastname: Ashfaq
authors.affiliation: Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas.
authors.forename: Mario
authors.initials: M
authors.lastname: de los Santos
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Healthcare System, Temple, Texas.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grant
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Healthcare System, Temple, Texas. Electronic address: demorrow@medicine.tamhsc.edu.
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002493:Central Nervous System Diseases / Q000209:etiology*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D019826:Cholic Acid / Q000378:metabolism; D004195:Disease Models, Animal; D017114:Liver Failure, Acute / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D027981:Symporters / Q000235:genetics / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D019826:Cholic Acid