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Thyroid hormone induction of human cholesterol 7 alpha-hydroxylase (Cyp7a1) in vitro.

ABSTRACT: Thyroid hormone (TH) modulates serum cholesterol by acting on TH receptor ?1 (TR?1) in liver to regulate metabolic gene sets. In rodents, one important TH regulated step involves induction of Cyp7a1, an enzyme in the cytochrome P450 family, which enhances cholesterol to bile acid conversion and plays a crucial role in regulation of serum cholesterol levels. Current models suggest, however, that Cyp7a1 has lost the capacity to respond to THs in humans. We were prompted to re-examine TH effects on cholesterol metabolic genes in human liver cells by a recent study of a synthetic TH mimetic which showed that serum cholesterol reductions were accompanied by increases in a marker for bile acid synthesis in humans. Here, we show that TH effects upon cholesterol metabolic genes are almost identical in mouse liver, mouse and human liver primary cells and human hepatocyte cell lines. Moreover, Cyp7a1 is a direct TR target gene that responds to physiologic TR levels through a set of distinct response elements in its promoter. These findings suggest that THs regulate cholesterol to bile acid conversion in similar ways in humans and rodent experimental models and that manipulation of hormone signaling pathways could provide a strategy to enhance Cyp7a1 activity in human patients.

SUBMITTER: Lammel Lindemann JA

PROVIDER: S-EPMC4180720 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Thyroid hormone induction of human cholesterol 7 alpha-hydroxylase (Cyp7a1) in vitro.

Lammel Lindemann Jan A JA Angajala Anusha A Engler David A DA Webb Paul P Ayers Stephen D SD

Molecular and cellular endocrinology 20140225 1-2

Thyroid hormone (TH) modulates serum cholesterol by acting on TH receptor β1 (TRβ1) in liver to regulate metabolic gene sets. In rodents, one important TH regulated step involves induction of Cyp7a1, an enzyme in the cytochrome P450 family, which enhances cholesterol to bile acid conversion and plays a crucial role in regulation of serum cholesterol levels. Current models suggest, however, that Cyp7a1 has lost the capacity to respond to THs in humans. We were prompted to re-examine TH effects on ...[more]

PMID: 24582860

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Project description:BACKGROUND:CYP7A1 (cholesterol 7?-hydroxylase) catalyzes the rate-limiting step in bile acid biosynthesis from cholesterol-a main pathway for cholesterol removal from the body. CYP7A1 single-nucleotide polymorphisms (SNPs) are associated with total cholesterol and LDL (low-density lipoprotein) levels, risk of cardiovascular diseases, and other phenotypes; however, results are inconsistent, and causative variants remain uncertain, except for a frequent promoter SNP (rs3808607). METHODS:We used chromatin conformation capture (4C assay), chromatin immunoprecipitation qPCR assay in hepatocytes, and CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing in hepatocellular carcinoma cell line cells to identify regulatory regions for CYP7A1. We then screened for SNPs located in regulatory regions, testing effects on reporter gene assays and on hepatic CYP7A1 expression by measuring allelic mRNA expression imbalance. RESULTS:4C assays showed several regions interacting with CYP7A1 promoter. CRISPR-mediated genome editing in hepatocellular carcinoma cell line cells revealed a novel CYP7A1 enhancer and a repressor region, located >10 kb downstream of the CYP7A1 promoter. SNP screening with an allelic mRNA expression imbalance in human livers and reporter gene assays identified a frequent functional SNP (rs9297994) located in the downstream CYP7A1 enhancer region. SNP rs9297994 is in high linkage disequilibrium with promoter SNP rs3808607 but has opposite effects on CYP7A1 mRNA expression. Their combined effects using a 2-SNP model robustly associate with hepatic CYP7A1 mRNA expression, ranging >2 orders of magnitude. Moreover, only the 2-SNP model, but not each SNP alone, is significantly associated with LDL levels, risk of coronary artery disease, statin response, and diabetes mellitus in several clinical cohorts, including CATHGEN (Catheterization Genetics) and Framingham. CONCLUSIONS:Two interacting regulatory SNPs modulate CYP7A1 expression and are associated with risk of coronary artery disease and diabetes mellitus.

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.

Dataset Information

Thyroid hormone induction of human cholesterol 7 alpha-hydroxylase (Cyp7a1) in vitro.

Publications

Thyroid hormone induction of human cholesterol 7 alpha-hydroxylase (Cyp7a1) in vitro.

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