Proteasome inhibition protects against diet-induced gallstone formation through modulation of cholesterol and bile acid homeostasis

Abstract

Gallstone disease is one of the most prevalent and costly gastrointestinal disorders worldwide. Gallstones are formed in the biliary system by cholesterol secretions in bile, which result from excess cholesterol, a deficiency in bile salts or a combination of the two. The present study examined the effects of proteasome inhibition on gallstone formation using the proteasome inhibitors bortezomib (BT) and carfilzomib (CF). C57BL/6J mice were fed a lithogenic diet to generate gallstones and injected with BT or CF for 12 weeks. After 12 weeks of the lithogenic diet, 8 out of the 10 mice in the control group had developed gallstones, whereas none of the mice who received proteasome inhibitors had developed gallstones. Notably, the expression of genes associated with cholesterol synthesis (sterol regulatory element‑binding protein‑2 and 3‑hydroxy‑3‑methylglutaryl‑CoA reductase), cholesterol secretion [ATP‑binding cassette subfamily G member 5 (ABCG5) and ABCG8] and bile acid synthesis [cytochrome P450 family 7 subfamily A member 1 (Cyp7a1), Cyp7b1, Cyp27a1 and Cyp8b1] was reduced in the livers of mice injected with BT or CF. Cyp7a1 encodes cholesterol 7α‑hydroxylase, the rate‑limiting enzyme in the synthesis of bile acid from cholesterol. The present study therefore measured the expression levels of transcription factors that are known to inhibit Cyp7a1 expression, namely farnesoid X receptor (FXR), pregnane X receptor (PXR) and small heterodimer partner (SHP). Although FXR, PXR and SHP expression was predicted to increase in the presence of proteasome inhibitors, the expression levels were actually reduced; thus, it was concluded that they were not involved in the proteasome inhibition‑induced regulation of Cyp7a1. Further investigation of the mitogen‑activated protein kinase and protein kinase A (PKA) signaling pathways in human hepatoma cells revealed that proteasome inhibition‑induced c‑Jun N‑terminal kinase (JNK) phosphorylation reduced CYP7A1 and CYP27A1 expression. In addition, reduced PKA phosphorylation as a result of proteasome inhibition regulated ABCG5 and ABCG8 expression. In conclusion, these findings suggest that proteasome inhibition regulates cholesterol and biliary metabolism via the JNK and PKA pathways, and is a promising therapeutic strategy to prevent gallstone disease.

Assessment of Effects of Thyrotoxicosis on Gallstone Formation in Rabbits

“…Studies have shown that CSI was more important than cholesterol levels in cholelithiasis formation (5,20). These findings were attributed to an increase in cholesterol and bile salt deficiency (10), and our results are consistent with those findings. We found that the bile cholesterol levels were lower even in the rabbit groups receiving thyroxine hormones because the bile acid levels were much lower in these groups.…”

“…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). A gallstone starts with a nucleus formation, and it has been shown that nucleus formation time was shortened by a lithogenic diet (4,11).…”

“…A gallstone starts with a nucleus formation, and it has been shown that nucleus formation time was shortened by a lithogenic diet (4,11). There are some additional factors, including mucus, calcium, and transferrin that accelerate gallstone nucleus formation, but some other factors such as bile and fatty acids prevent it (4,10,11).…”

Effect of Bamboo Leaf Extract on Antioxidant Status and Cholesterol Metabolism in Broiler Chickens

“…Cholesterol homeostasis is very important for broilers, as its metabolism dysfunction will lead to atherosclerosis, bile duct blockage or gallstones and other diseases [43,44]. The TC, TG, HDL-c, and LDL-c contents in serum are important indicators of cholesterol metabolism.…”

Human cytochrome P450 enzymes 5–51 as targets of drugs and natural and environmental compounds: mechanisms, induction, and inhibition – toxic effects and benefits

“…The CYP7A1 gene is highly regulated, as might be expected for an enzyme with a central role in the clearance of an important sterol (Guengerich 2015, Zhang, Zhao, et al 2017, Zhang, Jackson, et al 2017, Zhang, Wang, et al 2018, Lee et al 2018). Transcription of the CYP7A1 gene is stimulated by dietary cholesterol in rodents (Horton et al 1995).…”