Overexpression of cholesterol 7α-hydroxylase promotes hepatic bile acid synthesis and secretion and maintains cholesterol homeostasis

Abstract

We reported previously that mice overexpressing cytochrome P450 7a1 (Cyp7a1; Cyp7a1-tg mice) are protected against high fat diet-induced hypercholesterolemia, obesity, and insulin resistance. Here, we investigated the underlying mechanism of bile acid signaling in maintaining cholesterol homeostasis in Cyp7a1-tg mice. Cyp7a1-tg mice had two-fold higher Cyp7a1 activity and bile acid pool than did wild-type mice. Gallbladder bile acid composition changed from predominantly cholic acid (57%) in wild-type to chenodeoxycholic acid (54%) in Cyp7a1-tg mice. Cyp7a1-tg mice had higher biliary and fecal cholesterol and bile acid secretion rates than did wild-type mice. Surprisingly, hepatic de novo cholesterol synthesis was markedly induced in Cyp7a1-tg mice but intestine fractional cholesterol absorption in Cyp7a1-tg mice remained the same as wild-type mice despite the presence of increased intestine bile acids. Interestingly, hepatic but not intestinal expression of several cholesterol (adenosine triphosphatebinding cassette G5/G8 [ABCG5/G8], scavenger receptor class B, member 1) and bile acid (ABCB11) transporters were significantly induced in Cyp7a1-tg mice. Treatment of mouse or human hepatocytes with a farnesoid X receptor (FXR) agonist GW4064 or bile acids induced hepatic Abcg5/g8 expression. A functional FXR binding site was identified in the Abcg5 gene promoter. Study of tissue-specific Fxr knockout mice demonstrated that loss of the Fxr gene in the liver attenuated bile acid induction of hepatic Abcg5/g8 and gallbladder cholesterol content, suggesting a role of FXR in the regulation of cholesterol transport. Conclusion: This study revealed a new mechanism by which increased Cyp7a1 activity expands the hydrophobic bile acid pool, stimulating hepatic cholesterol synthesis and biliary cholesterol secretion without increasing intestinal cholesterol absorption. This study demonstrated that Cyp7a1 plays a critical role in maintaining cholesterol homeostasis and underscores the importance of bile acid signaling in regulating overall cholesterol homeostasis. (HEPATOLOGY 2011;53:996-1006)

Anti-obesity Effect of Alkaline Reduced Water in High Fat-Fed Obese Mice

“…26) Our data are strongly supported by recent studies that show how the induction of CYP7A1 gene expression prevents high-fat DIO, fatty liver and insulin resistance. 25,27) ARW intake increased HMG-CoA reductase expression although insignificant, we think this is in compatible to previous finding that hepatic HMG-CoA reductase expression is markedly down-regulated in HFD mice. 28,29) Together, we suggest that, ARW intake may influence cholesterol homeostasis in the liver via regulation of CYP7A1 activity.…”

Cholesterol 7α-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders

“…2A, lower panel), though fasting glucose levels prior to the test were reduced in Cyp7a1 / mice. These data are somewhat surprising, as we previously reported that Cyp7a1-transgenic mice also have improved insulin sensitivity and glucose tolerance (21,22). When fed 0.03% CA for 10 weeks, the improved glucose tolerance in Cyp7a1 / mice was attenuated (Fig.…”

“…In Cyp7a1-transgenic mice, liver de novo cholesterol synthesis was stimulated but fatty acid synthesis was decreased, coupled with increased biliary bile acid and cholesterol secretion to maintain bile acid and cholesterol homeostasis (22). To further study bile acid synthesis in liver metabolism and disease, we generated Cyp7a1 / mice in a C57BL/6J genetic background to test to determine whether Cyp7a1 / mice develop symptoms of metabolic syndrome expected from high-fat/high-cholesterol diet feeding.…”

Hypocholesterolaemic Effects of Probiotics

“…They also found expressions of the LDL-receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase were marginally affected by feeding L. plantarum KCTC3928 but interestingly the gene expression and protein levels of CYP7A1 were significantly upregulated [5]. The gene CYP7A1 encodes for cholesterol 7-α-hydroxylase, the rate-limiting enzyme in the bile acid biosynthetic pathway in liver and thus controls cholesterol and bile acid homeostasis [65]. The increase in cholesterol 7-α-hydroxylase may explain the increase in fecal bile excretion and low serum cholesterol level observed by Jeun et al [5] since bile acid formation is a major pathway of cholesterol excretion from the body.…”