title: Prevention of gallbladder hypomotility via FATP2 inhibition protects from lithogenic diet-induced cholelithiasis.
abstract: Gallstone disease is a widespread disorder costing billions for annual treatment in the United States. The primary mechanisms underlying gallstone formation are biliary cholesterol supersaturation and gallbladder hypomotility. The relative contribution of these two processes has been difficult to dissect, as experimental lithogenic diets cause both bile supersaturation and alterations in gallbladder motility. Importantly, there is no mechanistic explanation for obesity as a major risk factor for cholelithiasis. We discovered that lithogenic diets induce ectopic triacylglycerol (TAG) accumulation, a major feature of obesity and a known muscle contraction impairing condition. We hypothesized that prevention of TAG accumulation in gallbladder walls may prevent gallbladder contractile dysfunction without impacting biliary cholesterol saturation. We utilized adeno-associated virus-mediated knock down of the long-chain fatty acid transporter 2 (FATP2; Slc27A2), which is highly expressed by gallbladder epithelial cells, to downregulate lithogenic diet-associated TAG accumulation. FATP2-knockdown significantly reduced gallbladder TAG, but did not affect key bile composition parameters. Importantly, measurements with force displacement transducers showed that contractile strength in FATP2-knockdown gallbladders was significantly greater than in control gallbladders following lithogenic diet administration, and the magnitude of this effect was sufficient to prevent the formation of gallstones. FATP2-driven fatty acid uptake and the subsequent TAG accumulation in gallbladder tissue plays a pivotal role in cholelithiasis, and prevention of this process can protect from gallstone formation, even in the context of supersaturated bile cholesterol levels, thus pointing to new treatment approaches and targets.
authors.affiliation: Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
authors.forename: Kevin M
authors.identifier: 0000-0002-3543-3266
authors.initials: KM
authors.lastname: Tharp
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; and.
authors.forename: Amin
authors.initials: A
authors.lastname: Khalifeh-Soltani
authors.affiliation: Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
authors.forename: Hyo Min
authors.initials: HM
authors.lastname: Park
authors.affiliation: Eli Lilly and Company.
authors.forename: David A
authors.initials: DA
authors.lastname: Yurek
authors.affiliation: Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
authors.forename: Alaric
authors.initials: A
authors.lastname: Falcon
authors.affiliation: Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
authors.forename: Louis
authors.initials: L
authors.lastname: Wong
authors.affiliation: Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
authors.forename: Rouying
authors.initials: R
authors.lastname: Feng
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; and.
authors.forename: Kamran
authors.initials: K
authors.lastname: Atabai
authors.affiliation: Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California; astahl@berkeley.edu.
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
mesh_terms: D000818:Animals; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D015536:Down-Regulation; D005704:Gallbladder / Q000378:metabolism* / Q000503:physiopathology; D042882:Gallstones / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D014280:Triglycerides; D003066:Coenzyme A Ligases; C525186:FATP2 protein, mouse
keywords: FFA; contractility; gallstones; triacylglycerol; uptake