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Regulation of cholesterol and bile acid homeostasis by the cholesterol 7?-hydroxylase/steroid response element-binding protein 2/microRNA-33a axis in mice.

ABSTRACT: Bile acid synthesis not only produces physiological detergents required for intestinal nutrient absorption, but also plays a critical role in regulating hepatic and whole-body metabolic homeostasis. We recently reported that overexpression of cholesterol 7?-hydroxylase (CYP7A1) in the liver resulted in improved metabolic homeostasis in Cyp7a1 transgenic (Cyp7a1-tg) mice. This study further investigated the molecular links between bile acid metabolism and lipid homeostasis. Microarray gene profiling revealed that CYP7A1 overexpression led to marked activation of the steroid response element-binding protein 2 (SREBP2)-regulated cholesterol metabolic network and absence of bile acid repression of lipogenic gene expression in livers of Cyp7a1-tg mice. Interestingly, Cyp7a1-tg mice showed significantly elevated hepatic cholesterol synthesis rates, but reduced hepatic fatty acid synthesis rates, which was accompanied by increased (14) C-glucose-derived acetyl-coenzyme A incorporation into sterols for fecal excretion. Induction of SREBP2 also coinduces intronic microRNA-33a (miR-33a) in the SREBP2 gene in Cyp7a1-tg mice. Overexpression of miR-33a in the liver resulted in decreased bile acid pool, increased hepatic cholesterol content, and lowered serum cholesterol in mice.This study suggests that a CYP7A1/SREBP2/miR-33a axis plays a critical role in regulation of hepatic cholesterol, bile acid, and fatty acid synthesis. Antagonism of miR-33a may be a potential strategy to increase bile acid synthesis to maintain lipid homeostasis and prevent nonalcoholic fatty liver disease, diabetes, and obesity.

SUBMITTER: Li T

PROVIDER: S-EPMC3735649 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Regulation of cholesterol and bile acid homeostasis by the cholesterol 7α-hydroxylase/steroid response element-binding protein 2/microRNA-33a axis in mice.

Li Tiangang T Francl Jessica M JM Boehme Shannon S Chiang John Y L JY

Hepatology (Baltimore, Md.) 20130731 3

<h4>Unlabelled</h4>Bile acid synthesis not only produces physiological detergents required for intestinal nutrient absorption, but also plays a critical role in regulating hepatic and whole-body metabolic homeostasis. We recently reported that overexpression of cholesterol 7α-hydroxylase (CYP7A1) in the liver resulted in improved metabolic homeostasis in Cyp7a1 transgenic (Cyp7a1-tg) mice. This study further investigated the molecular links between bile acid metabolism and lipid homeostasis. Mic ...[more]

PMID: 23536474

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Project description:BackgroundDuring the postnatal feeding period, formula-fed infants have higher cholesterol synthesis rates and lower circulating cholesterol concentrations than their breastfed counterparts. Although this disparity has been attributed to the uniformly low dietary cholesterol content of typical infant formulas, little is known of the underlying mechanisms associated with this altered cholesterol metabolism phenotype.ObjectiveWe aimed to determine the molecular etiology of diet-associated changes in early-life cholesterol metabolism with the use of a postnatal piglet feeding model.MethodsTwo-day-old male and female White-Dutch Landrace piglets were fed either sow milk (Sow group) or dairy-based (Milk group; Similac Advance powder) or soy-based (Soy group; Emfamil Prosobee Lipil powder) infant formulas until day 21. In addition to measuring serum cholesterol concentrations, hepatic and intestinal genes involved in enterohepatic circulation of cholesterol and bile acids were analyzed by real-time reverse-transcriptase polymerase chain reaction and Western blot. Bile acid concentrations were measured by liquid chromatography-mass spectrometry in serum, liver, and feces.ResultsCompared with the Sow group, hepatic cholesterol 7α hydroxylase (CYP7A1) protein expression was 3-fold higher in the Milk group (P < 0.05) and expression was 10-fold higher in the Soy group compared with the Milk group (P < 0.05). Likewise, fecal bile acid concentrations were 3-fold higher in the Soy group compared with the Milk group (P < 0.05). Intestinal mRNA expression of fibroblast factor 19 (Fgf19) was reduced in the Milk and Soy groups, corresponding to 54% and 67% decreases compared with the Sow group. In the Soy group, small heterodimer protein (SHP) protein expression was 30% lower compared with the Sow group (P < 0.05).ConclusionsThese results indicate that formula feeding leads to increased CYP7A1 protein expression and fecal bile acid loss in neonatal piglets, and this outcome is linked to reduced efficacy in inhibiting CYP7A1 expression through FGF19 and SHP transcriptional repression mechanisms.

Project description: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 triphosphate-binding 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.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.

Project description:ObjectiveTo investigate the cholesterol 7α-hydroxylase gene ( CYP7A1)-204A/C single nucleotide polymorphism and its relationship with the blood lipid levels of pregnant women with gestational diabetes mellitus (GDM) and normal pregnant women.MethodsThe genotype and allele frequencies of CYP7A1-204A/C gene polymorphism of 1037 normal pregnant women, the normal controls, and 627 pregnant women with GDM were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and blood glucose (Glu) were measured by enzymatic assay. Chemiluminescence determination of plasma insulin (Ins) was conducted. Apolipoproteins A1 (apoA1) and B (apoB) were measured by the turbidimetric immunoassay.ResultsAllele frequencies of A and C at the CYP7A1-204A/C polymorphic locus were 0.586 and 0.414, respectively, in the GDM group and 0.557 and 0.443, respectively in the control group. The distribution of genotype frequencies in both groups showed conformity with the Hardy-Weinberg principle. There was no significant difference in allele and genotype frequencies between the GDM group and the control group. In the control group, carriers of the genotype AA were associated with significantly higher concentrations of apoA1 and lower levels of Ins and homeostatic model assessment of insulin resistance (HOMA-IR) compared with those with genotype CC (all P<0.05). In the non-obese subgroup of the control subjects, carriers of the genotype CC were associated with significantly higher plasma TG or apoA1 levels compared with those with genotype AA ( P<0.05). In the GDM group, carriers with genotype AA of CYP7A1-204A/C polymorphism had elevated levels of gestational weight gain (GWG) compared with those with genotype CC ( P<0.05).ConclusionThese results suggest that 204A/C polymorphism in the CYP7A1 gene is not associated with GDM, but may be closely associated with gestational weight gain in pregnant women with GDM. Variants in this locus are strongly associated with plasma apoA1, Ins, and HOMA-IR levels in the controls and elevated plasma TG levels in non-obese controls.

Dataset Information

Regulation of cholesterol and bile acid homeostasis by the cholesterol 7?-hydroxylase/steroid response element-binding protein 2/microRNA-33a axis in mice.

Publications

Regulation of cholesterol and bile acid homeostasis by the cholesterol 7α-hydroxylase/steroid response element-binding protein 2/microRNA-33a axis in mice.

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