Gallstone disease is a widespread disorder costing billions in annual treatment costs. The primary mechanisms underlying gallstone formation are biliary cholesterol supersaturation and gallbladder hypo-motility. 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 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 AAV mediated knock down of the long-chain fatty acid transporter 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 were 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 super saturated bile cholesterol levels, thus pointing to new treatment approaches and targets.
- Copyright © 2016, American Journal of Physiology- Gastrointestinal and Liver Physiology