Osteopontin deficiency protects mice from cholesterol gallstone formation by reducing expression of intestinal NPC1L1

Abstract

Homeostasis of cholesterol is regulated by absorption in the intestine and synthesis in the liver. The authors previously demonstrated that OPN (osteopontin) exhibits the ability to alter hepatic cholesterol metabolism, thus affecting cholesterol gallstone formation in mice. The present study investigated the role of OPN in cholesterol gallstone formation, focusing on its effect on intestinal absorption of cholesterol. OPN gene knockout (OPN−/−) mice and wild-type mice were respectively fed with a chow or lithogenic diet (LD) for 8 weeks. Following an 8-week LD period, the incidence of gallstone, bile composition, level of serum and fecal lipids and the expression of intestinal associated genes were analyzed. OPN−/− mice were protected from gallstone formation induced by 8 weeks' LD-feeding. This protective effect from OPN deficiency was associated with alterations in bile composition, including a reduced concentration of biliary cholesterol. Additionally, plasma cholesterol level was decreased in LD-fed OPN−/− mice. The alterations primarily resulted from the decreased expression of intestinal Niemann-Pick C1-like (NPC1 L) 1, which is important in the intestinal absorption of cholesterol. The present study demonstrated that OPN deficiency reduced intestinal absorption of cholesterol by suppressing the expression of NPC1L1, thus protecting mice from cholesterol gallstone formation.

Effect of hepatic NPC1L1 on cholesterol gallstone disease and its mechanism

“…The role of intestinal NPC1L1 in efficient cholesterol absorption has been well demonstrated [ 10 ]. Decreased expression of intestinal NPC1L1 can reduce plasma cholesterol levels, thereby reducing the risk of CGD in mice [ 22 ]. Conversely, hepatic NPC1L1 can prevent CGD through the down-regulation of the NPC2 protein, which facilitates cholesterol nucleation [ 23 , 24 ].…”

Recent advances in understanding and managing cholesterol gallstones

“…The mechanism involves reduced amounts of absorbed cholesterol reaching the liver through the entero-hepatic circulation and, in turn, decreased biliary cholesterol saturation 79 – 81 . Additionally, deficiency of osteopontin (OPN) (a soluble cytokine and a matrix-associated protein detectable in the majority of tissues and body fluids) in OPN −/− mice on lithogenic diet reduces the intestinal absorption of cholesterol through a suppressed expression of NPC1L1, preventing cholesterol gallstone formation 111 .…”

Osteopontin Exacerbates High-Fat Diet-Induced Metabolic Disorders in a Microbiome-Dependent Manner

“…For instance, OPN-deficient mice displayed less severe hepatic steatosis ( 13 ). A reduced absorption of cholesterol was also observed in OPN-deficient mice, and this prevented gallstone formation ( 14 ). Furthermore, the level of OPN is regarded to be increased in obesity-associated diseases ( 15 , 16 ).…”