CAV1 Prevents Gallbladder Cholesterol Crystallization by Regulating Biosynthesis and Transport of Bile Salts

Abstract

Cholesterol gallstone disease (CGD) is a hepatobiliary disorder which results from a biochemical imbalance in the gallbladder bile. Here we show that loss of CAV1 sensitized mice to lithogenic diet-induced gallbladder cholesterol crystallization, which was associated with dysregulation of several hepatic transporters that efflux cholesterol, phospholipids, and bile salts. The combined effect of increased biliary cholesterol concentration and decreased biliary bile salt secretion in CAV1(-/-) mice led to an increased cholesterol saturation index and the formation of cholesterol crystals. At the signaling level, the ERK/AP-1 pathway seems to mediate the effects of CAV1 on biliary BA homeostasis and might be developed as a therapeutic target for CGD. We propose that CAV1 is an anti-lithogenic factor and that the CAV1(-/-) mice may offer a convenient CGD model to develop therapeutic interventions for this disease. J. Cell. Biochem. 117: 2118-2127, 2016. © 2016 Wiley Periodicals, Inc.

FGF15 promotes hepatic NPC1L1 degradation in lithogenic diet-fed mice

“…For drug treatment, ezetimibe (EZE, 5 mg/kg, oral dosing, once a day) was given 1 week prior to the beginning of the LD or HFCD. Ezetimibe is a drug with limited water solubility, thus the components of the HFCD or LD diet were thoroughly mixed with ezetimibe during diet preparation and the bacon-flavoured dough pills were produced by Double Lion CO., LTD (Suzhou，China) for the oral administration of ezetimibe [ 8 ]. The recombinant FGF15 (100 μg/kg/day, Abcam ab206457; Trumpington, UK) or highly selective covalent FGFR4 inhibitor H3B-6527 [ 22 ] (1702259–66-2, 5 mg/kg/day, once a day, i.p.…”

“…Niemann-Pick C1-like 1 (NPC1L1) is a polytopic transmembrane protein that contain a sterol-sensing domain, essential to promote the ability to absorb cholesterol [ 4 , 5 ]. As an inhibitor of NPC1L1 [ 6 ], ezetimibe (EZE) can effectively lower the plasma LDL-cholesterol [ 7 ] and decrease the risk of CGD, as shown in the previous study [ 8 ]. In contrast to rodent NPC1L1, human NPC1L1 is highly expressed in the liver [ 9 ].…”

Adeno-associated virus-based caveolin-1 delivery via different routes for the prevention of cholesterol gallstone formation

“…CAV1 can also be detected in endosomes, lipid droplets, mitochondria, endoplasmic reticulum, and other intracellular compartments, suggesting that CAV1 may act in a caveolae-independent manner in the liver [ 3 ]. CAV1 is thought to play a key role in cholesterol gallstone disease (CGD), nonalcoholic fatty liver disease (NAFLD), and other diseases associated with high cholesterol levels [ 2 – 6 ].…”

“…Although the exact molecular mechanism remains unclear, excessive accumulation of biliary cholesterol and abnormal cholesterol nucleation time (NT) are considered relevant factors for CGD development [ 7 ]. In the murine CGD model, we observed an increase in the secretion of biliary cholesterol, a decrease in the synthesis of bile acids, and an increase in the bile cholesterol saturation index (CSI)[ 6 ]. Using CAV1 knockout mice can significantly increase the incidence of CGD after 4 weeks of a lithogenetic diet [ 6 ].…”

Assessment of Effects of Thyrotoxicosis on Gallstone Formation in Rabbits

“…Other risk factors for cholesterol gallstones include age, gender, genetics, obesity, weight loss, and bowel disease (7). The association between serum lipid levels and gallstone has been reported and studies have shown that cholesterol saturation index (CSI), which is one of the main factors for gallstone formation, was more crucial than cholesterol concentration (8,9). CSI is described as the ratio of measured concentration of cholesterol to the measured concentration of bile salts plus phospholipid (10).…”