Nuclear Receptor Variants in Liver Disease

Müllenbach, Roman; Weber, Susanne N.; Lammert, Frank

doi:10.1155/2012/934707

Cited by 6 publications

(4 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We did also not detect any expression difference for the transcription factor Srebf1 , which activates the expression of genes dedicated to sterol, triglyceride, and PC synthesis (40) and is repressed by PC (13), between Abcb4 –/– and wild‐type mice in vivo. In contrast, the expression of Ppargc1a and the transcription factor Foxo1 , both involved in the regulation of gluconeogenesis (41), is induced.…”

Section: Resultsmentioning

confidence: 99%

The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis

et al. 2012

Self Cite

View full text Add to dashboard Cite

The hepatic phosphatidylcholine (PC) transporter ATP-binding cassette (ABC) B4 flops PC from hepatocytes into bile, and its dysfunction causes chronic cholestasis and fibrosis. Because a nuclear receptor-dependent PC pathway has been determined to exert antidiabetic effects, we now analyzed the role of ABCB4 in glucose metabolism. We bred congenic Abcb4-knockout (Abcb4(-/-)) mice on the fibrosis-susceptible BALB/cJ background. Knockout mice and wild-type controls were phenotyped by measuring plasma glucose concentrations, intraperitoneal glucose tolerance, hepatic RNA expression profiles, and liver histology. In addition, 4 procholestatic ABCB4 gene variants were correlated with blood glucose levels in 682 individuals from 2 independent European cohorts. Systemic glucose levels differ significantly between Abcb4(-/-) mice and wild-type controls, and knockout mice display improved glucose tolerance with significantly lower area under the curve values on intraperitoneal glucose challenge. Of note, hepatic expression of the antidiabetic nuclear receptor 5A2 (LRH-1) is induced consistently in Abcb4(-/-) mice, and its specific rare PC ligands are detected in liver by mass spectrometry imaging. In humans, serum glucose levels are associated significantly with the common ABCB4 variant c.711A>T. In summary, ABCB4 might play a critical role in glucose homeostasis in mice and humans. We speculate that the effects could be mediated via LRH-1-dependent PC pathways.

show abstract

Section: Resultsmentioning

confidence: 99%

The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“… 59 Secondly, FXR promotes fatty acid consumption by activating fatty acid β-oxidation. 60 , 61 Thirdly, the FXR/SHP pathway inhibits PEPCK and G6Pase, thereby suppressing gluconeogenesis and enhancing glucose tolerance and insulin sensitivity. 62 The results suggest that davidiin may modulate the bile acid pool by promoting CYP3A4 expression, leading to a hypoglycemic effect through the FXR-GLP-1/PPAR/SHP pathway.…”

Section: Discussionmentioning

confidence: 99%

Unveiling the Pharmacological Mechanisms of Davidiin’s Anti-Diabetic Efficacy in Streptozotocin-Treated Rats: A Comprehensive Analysis of Serum Metabolome

Li,

Zhou,

Huang

et al. 2024

DDDT

View full text Add to dashboard Cite

Background Polygonum capitatum Buch.-Ham. ex D. Don ( P. capitatum ), a traditional herb used in Miao medicine, is renowned for its heart-clearing properties. Davidiin, the primary bioactive component (approximately 1%), has been used to treat various conditions, including diabetes. Given its wide range of effects and the diverse biomolecular pathways involved in diabetes, there is a crucial need to study how davidiin interacts with these pathways to better understand its anti-diabetic properties. Materials and Methods Diabetic rats were induced using a high-fat diet and streptozotocin (STZ) administered intraperitoneally at 35 mg/kg. Out of these, 24 rats with blood glucose levels ≥ 11.1 mmol/L and fasting blood glucose levels ≥ 7.0 mmol/L were selected for three experimental groups. These groups were then treated with either metformin (gavage, 140 mg/kg) or davidiin (gavage, 90 mg/kg) for four weeks. After the treatment period, we measured body weight, blood glucose levels, and conducted untargeted metabolic profiling using UPLC-QTOF-MS. Results Davidiin has been shown to effectively treat diabetes by reducing blood glucose levels from 30.2 ± 2.6 mmol/L to 25.1 ± 2.4 mmol/L (P < 0.05). This effect appears stronger than that of metformin, which lowered glucose levels to 26.5 ± 2.6 mmol/L. The primary outcomes of serum metabolomics are significant changes in lipid and lipid-like molecular profiles. Firstly, davidiin may affect phosphatide metabolism by increasing levels of phosphatidylinositol and sphingosine-1-phosphate. Secondly, davidiin could influence cholesterol metabolism by reducing levels of glycocholic acid and glycochenodeoxycholic acid. Lastly, davidiin might impact steroid hormone metabolism by increasing hepoxilin B3 levels and decreasing prostaglandins. Conclusion Our study demonstrates that davidiin modulates various lipid-related metabolic pathways to exert its anti-diabetic effects. These findings offer the first detailed metabolic profile of davidiin’s action mechanism, contributing valuable insights to the field of Traditional Chinese Medicine in the context of diabetes treatment.

show abstract

“…Based on the assumption that populations from both the Swiss study and our cohort are from a similar ethnic background, we speculate that the major [C] allele of ABCB11 c.1331 T > C might be a high-frequency low-risk contributor towards susceptibility for various complex liver diseases triggered by external stimuli and involving lipid metabolism [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

A frequent variant in the human bile salt export pump gene ABCB11 is associated with hepatitis C virus infection, but not liver stiffness in a German population

et al. 2012

Self Cite

View full text Add to dashboard Cite

BackgroundThe human ATP-binding cassette, subfamily B, member 11 (ABCB11) gene encodes the bile salt export pump, which is exclusively expressed at the canalicular membrane of hepatocytes. A frequent variant in the coding region, c.1331 T > C, leading to the amino acid exchange p.V444A, has been associated with altered serum bile salt levels in healthy individuals and predisposes homozygous carriers of the [C] allele for obstetric cholestasis. Recently, elevated bile salt levels were shown to be significantly associated with rates and risk of cirrhosis in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon-α2 and ribavirin, suggesting a potential role for bile salt levels in HCV treatment outcomes and in the fibrogenic evolution of HCV-related liver disease. The aim of this study was to investigate a possible association of ABCB11 c.1331 T > C with hepatitis C virus (HCV) infection and fibrosis stages as assessed by non-invasive transient elastography in a German cohort of patients.MethodsABCB11 c.1331 T > C genotype was determined by allelic discrimination assay in 649 HCV infected cases and 413 controls. Overall, 444 cases were staged for fibrotic progression by measurement of liver stiffness.ResultsHomo- or heterozygous presence of the frequent [C] allele was associated with HCV positivity (OR = 1.41, CI = 1.02 - 1.95, p = 0.037). No association was detectable between the ABCB11 c.1331 T > C genotype and increased liver stiffness.ConclusionsOur data confirm that homozygous presence of the major [C] allele of ABCB11 c.1331 T > C is a genetic susceptibility factor for HCV infection, but not for liver fibrosis.

show abstract

Nuclear Receptor Variants in Liver Disease

Cited by 6 publications

References 87 publications

The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis

The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis

Unveiling the Pharmacological Mechanisms of Davidiin’s Anti-Diabetic Efficacy in Streptozotocin-Treated Rats: A Comprehensive Analysis of Serum Metabolome

A frequent variant in the human bile salt export pump gene ABCB11 is associated with hepatitis C virus infection, but not liver stiffness in a German population

Contact Info

Product

Resources

About