Vitamin D Receptor Activation Down-regulates the Small Heterodimer Partner and Increases CYP7A1 to Lower Cholesterol

Chow, Edwin; Magomedova, Lilia; Quach, Holly P.; Patel, Rucha; Durk, Matthew R.; Fan, Jianghong; Maeng, Han Joo; Irondi, Kamdi; Anakk, Sayeepriyadarshini; Moore, David D.; Cummins, Carolyn L.; Pang, K. Sandy

doi:10.1053/j.gastro.2013.12.027

Cited by 75 publications

(99 citation statements)

References 33 publications

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“…Plasma alanine aminotransaminase (ALT) from fresh plasma samples were immediately quantified by the ALT kit (Bioquant, Nashville, TN), and plasma and liver cholesterol and liver triglyceride levels were measured using total cholesterol (Wako Diagnostics, Richmond, VA, and Thermo Scientific, Rockford, IL, respectively) and triglyceride (Thermo Scientific) kits, as previously described by Chow et al (2014). Total and conjugated bilirubin in bile were assayed by the bilirubin assay kit (SigmaAldrich Canada) after a 15-fold dilution with saline.…”

Section: Instability Of the Chimeric Humanized Liver Mouse Modelmentioning

confidence: 99%

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Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Chow

Quach

Zhang

et al. 2016

J Pharmacol Exp Ther

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The humanized liver mouse model is being exploited increasingly for human drug metabolism studies. However, its model stability, intercommunication between human hepatocytes and mouse nonparenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expressions have not been investigated. We examined these issues in FRGN [fumarylacetoacetate hydrolase (Fah2/2), recombination activating gene 2 (Rag22/2), and interleukin 2 receptor subunit gamma (IL-2rg 2/2) triple knockout] on nonobese diabetic (NOD) background] and chimeric mice: mFRGN and hFRGN (repopulated with mouse or human hepatocytes, respectively). hFRGN mice showed markedly higher levels of liver cholesterol, biliary bilirubin, and bile acids (liver, bile, and plasma; mainly human forms, but also murine bile acids) but lower transforming growth factor beta receptor 2 (TGFBR2) mRNA expression levels (10%) in human hepatocytes and other proliferative markers in mouse nonparenchymal cells (Tgf-b1) and cholangiocytes [plasma membrane-bound, G protein-coupled receptor for bile acids (Tgr5)], suggestive of irregular regeneration processes in hFRGN livers. Changes in gene expression in murine intestine, kidney, and brain of hFRGN mice, in particular, induction of intestinal farnesoid X receptor (Fxr) genes: fibroblast growth factor 15 (Fgf15), mouse ileal bile acid binding protein (Ibabp), small heterodimer partner (Shp), and the organic solute transporter alpha (Osta), were observed. Proteomics revealed persistence of remnant murine proteins (cyotchrome P450 7a-hydroxylase (Cyp7a1) and other enzymes and transporters) in hFRGN livers and suggest the likelihood of mouse activity. When compared with normal human liver tissue, hFRGN livers showed lower SHP mRNA and higher CYP7A1 (300%) protein expression, consequences of tb-and ta-muricholic acid-mediated inhibition of the FXR-SHP cascade and miscommunication between intestinal Fgf15 and human liver fibroblast growth factor receptor 4 (FGFR4), as confirmed by the unchanged hepatic pERK/total ERK ratio. Dysregulation of hepatocyte proliferation and bile acid homeostasis in hFRGN livers led to hepatotoxicity, gallbladder distension, liver deformity, and other extrahepatic changes, making questionable the use of the preparation for drug metabolism studies.

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Section: Instability Of the Chimeric Humanized Liver Mouse Modelmentioning

confidence: 99%

“…The bile acid extraction procedure was similar to that previously described by Chow et al (2014). On the last day of study, mice were fasted for 4 hours (from 9 AM to 1 PM).…”

Section: Instability Of the Chimeric Humanized Liver Mouse Modelmentioning

confidence: 99%

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Chow

Quach

Zhang

et al. 2016

J Pharmacol Exp Ther

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“…Participants with deficient levels of serum 25(OH)D were more likely to also have lower serum HDL-C levels ( p = 0.0003). Chow and colleagues [110] incubated human hepatocytes with 1,25(OH) 2 D 3 and found a reduction in cholesterol production due to an increase in cytochrome P450 enzyme 7A1 activation of the VDR.…”

Section: Findings: Evaluation Using Hill’s Criteria For Causalitymentioning

confidence: 99%

Does Sufficient Evidence Exist to Support a Causal Association between Vitamin D Status and Cardiovascular Disease Risk? An Assessment Using Hill’s Criteria for Causality

2014

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Serum 25-hydroxyvitamin D (25(OH)D) levels have been found to be inversely associated with both prevalent and incident cardiovascular disease (CVD) risk factors; dyslipidemia, hypertension and diabetes mellitus. This review looks for evidence of a causal association between low 25(OH)D levels and increased CVD risk. We evaluated journal articles in light of Hill’s criteria for causality in a biological system. The results of our assessment are as follows. Strength of association: many randomized controlled trials (RCTs), prospective and cross-sectional studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Consistency of observed association: most studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors in various populations, locations and circumstances. Temporality of association: many RCTs and prospective studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Biological gradient (dose-response curve): most studies assessing 25(OH)D levels and CVD risk found an inverse association exhibiting a linear biological gradient. Plausibility of biology: several plausible cellular-level causative mechanisms and biological pathways may lead from a low 25(OH)D level to increased risk for CVD with mediators, such as dyslipidemia, hypertension and diabetes mellitus. Experimental evidence: some well-designed RCTs found increased CVD risk factors with decreasing 25(OH)D levels. Analogy: the association between serum 25(OH)D levels and CVD risk is analogous to that between 25(OH)D levels and the risk of overall cancer, periodontal disease, multiple sclerosis and breast cancer. Conclusion: all relevant Hill criteria for a causal association in a biological system are satisfied to indicate a low 25(OH)D level as a CVD risk factor.

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“…Primers were checked against mRNA of mouse liver tissue and human hepatocellular carcinoma cells (HepG2) and water for specificity (see Supplementary Table 1). cDNA was synthesized from mRNA by a high-capacity cDNA synthesis kit as described previously (Chow et al, 2014) and quantified by quantitative polymerase chain reaction (Applied Biosystems 7500 series) using SYBR Green or Taqman for detection. For mRNA analyses of mouse liver genes in mouse liver and hepatocytes, the target genes of mouse liver and hepatocytes were normalized to that of cyclophilin.…”

mentioning

confidence: 99%

Functional Integrity of the Chimeric (Humanized) Mouse Liver: Enzyme Zonation, Physiologic Spaces, and Hepatic Enzymes and Transporters

Chow

Wang

Quach

et al. 2016

Drug Metabolism and Disposition

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Chimeric mouse liver models are useful in vivo tools for human drug metabolism studies; however, liver integrity and the microcirculation remain largely uninvestigated. Hence, we conducted liver perfusion studies to examine these attributes in FRGN [Fah(2/2), Rag2(2/2), and Il2rg(2/2), NOD strain] livers (control) and chimeric livers repopulated with mouse (mFRGN) or human (hFRGN) hepatocytes. In single-pass perfusion studies (2.5 ml/min), outflow dilution profiles of noneliminated reference indicators ( 51 Cr-RBC, 125 I-albumin, 14 C-sucrose, and 3 H-water) revealed preservation of flow-limited distribution and reduced water and albumin spaces in hFRGN livers compared with FRGN livers, a view supported microscopically by tightly packed sinusoids. With prograde and retrograde perfusion of harmol (50 mM) in FRGN livers, an anterior sulfation (Sult1a1) over the posterior distribution of glucuronidation (Ugt1a1) activity was preserved, evidenced by the 42% lower sulfation-to-glucuronidation ratio (HS/HG) and 14% higher harmol extraction ratio (E) upon switching from prograde to retrograde flow. By contrast, zonation was lost in mFRGN and hFRGN livers, with HS/HG and E for both flows remaining unchanged. Remnant mouse genes persisted in hFRGN livers (10%-300% those of FRGN). When hFRGN livers were compared with human liver tissue, higher UGT1A1 and MRP2, lower MRP3, and unchanged SULT1A1 and MRP4 mRNA expression were observed. Total Sult1a1/SULT1A1 protein expression in hFRGN livers was higher than that of FRGN livers, consistent with higher harmol sulfate formation. The composite data on humanized livers suggest a loss of zonation, lack of complete liver humanization, and persistence of murine hepatocyte activities leading to higher sulfation.

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Vitamin D Receptor Activation Down-regulates the Small Heterodimer Partner and Increases CYP7A1 to Lower Cholesterol

Cited by 75 publications

References 33 publications

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Does Sufficient Evidence Exist to Support a Causal Association between Vitamin D Status and Cardiovascular Disease Risk? An Assessment Using Hill’s Criteria for Causality

Functional Integrity of the Chimeric (Humanized) Mouse Liver: Enzyme Zonation, Physiologic Spaces, and Hepatic Enzymes and Transporters

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