Cholic acid mediates negative feedback regulation of bile acid synthesis in mice

Li-Hawkins, Jia; Gåfvels, Mats; Olin, Maria; Lund, Erik; Andersson, Ulla; Schuster, Gertrud U.; Björkhem, Ingemar; Russell, David W.; Eggertsen, Gösta

doi:10.1172/jci16309

Cited by 107 publications

(71 citation statements)

References 49 publications

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“…An increase in the TBMC fraction of the bile acid pool was also found in Cyp8b1 33 and liver receptor homologue-148 49 knockout mice. In both models, CYP8b1 is eliminated or dramatically reduced, leading to an increase in muricholic acid synthesis, and accumulation of TBMC in the bile acid pool.…”

Section: Discussionmentioning

confidence: 73%

“…Surprisingly, none of the mRNAs for key enzymes in the hepatic bile acid biosynthetic pathways (cholesterol 7α-hydroxylase (CYP7a1),30 31 sterol 27-hydroxylase (CYP27),32 sterol 12α-hydroxylase (CYP8b1)33 and oxysterol 7α-hydroxylase (CYP7b1)34) were significantly different in the G4ap mice as compared with the Wt -controls (figure 5a), suggesting that the shift in bile acid composition is not due to alterations in bile acid synthesis.…”

Section: Resultsmentioning

confidence: 99%

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Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine

Beuling

Kerkhof

Nicksa

et al. 2010

Gut

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Background and aims-The transcription factor GATA4 is expressed throughout most of the small intestine except distal ileum, and restricts expression of the apical sodium-dependent bile acid transporter (ASBT), the rate-limiting intestinal bile acid transporter, to distal ileum. The hypothesis was tested that reduction of GATA4 activity in mouse small intestine results in an induction of bile acid transport in proximal small intestine sufficient to restore bile acid absorption and homeostasis after ileocaecal resection (ICR).

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Section: Discussionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine

Beuling

Kerkhof

Nicksa

et al. 2010

Gut

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“…Loss of Cyp7a1 31, 32 or Cyp8b1 33 has been shown to reduce intestinal cholesterol absorption. Interestingly, hepatic Hnf4α deficiency reduced Cyp7a1 mRNA but not protein levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

Hepatic Hepatocyte Nuclear Factor 4α Is Essential for Maintaining Triglyceride and Cholesterol Homeostasis

Yin

et al. 2011

ATVB

137

150

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Objective-Loss-of-function mutations in human hepatocyte nuclear factor 4␣ (HNF4␣) are associated with maturity-onset diabetes of the young and lipid disorders. However, the mechanisms underlying the lipid disorders are poorly understood. In this study, we determined the effect of acute loss or augmentation of hepatic HNF4␣ function on lipid homeostasis. Methods and Results-We generated an adenovirus expressing LacZ (Ad-shLacZ) or short hairpin RNA of Hnf4␣ (Ad-shHnf4␣). Tail vain injection of C57BL/6J mice with Ad-shHnf4␣ reduced hepatic Hnf4␣ expression and resulted in striking phenotypes, including the development of fatty liver and a Ͼ80% decrease in plasma levels of triglycerides, total cholesterol, and high-density lipoprotein cholesterol. These latter changes were associated with reduced hepatic lipogenesis and impaired very-low-density lipoprotein secretion. Deficiency in hepatic Hnf4␣ did not affect intestinal cholesterol absorption despite decreased expression of genes involved in bile acid synthesis. Consistent with the loss-of-function data, overexpression of Hnf4␣ induced numerous genes involved in lipid metabolism in isolated primary hepatocytes. Interestingly, many of these HNF4␣-regulated genes were not induced in wild-type mice that overexpressed hepatic Hnf4␣. Because of selective gene regulation, mice overexpressing hepatic Hnf4␣ had unchanged plasma triglyceride levels and decreased plasma cholesterol levels. Conclusion-Loss of hepatic HNF4␣ results in severe lipid disorder as a result of dysregulation of multiple genes involved in lipid metabolism. In contrast, augmentation of hepatic HNF4␣ activity lowers plasma cholesterol levels but has no effect on plasma triglyceride levels because of selective gene regulation. N uclear receptors are ligand-activated transcription factors that regulate diverse physiological processes such as reproduction, development and metabolism. Hepatocyte nuclear factor 4␣ (HNF4␣, NR2A1) is a member of the nuclear receptor superfamily. It is highly expressed in the liver, with lower levels in the kidney, intestine, and pancreatic ␤ cells. 1,2 Like other members of the nuclear receptor superfamily, HNF4␣ has a highly conserved DNA-binding domain and a variable ligand-binding domain. However, HNF4␣ is known to be constitutively active. Structural analysis of the ligand-binding domain of HNF4␣ indicates the C14 to C18 long-chain fatty acids are tightly bound to the hydrophobic pocket 3,4 and cannot be dissociated from the receptor under nondenaturing conditions. 4 Recent data also show that linoleic acid selectively occupies the binding pocket of ligand-binding domain but does not affect the transcriptional activity of HNF4␣. 5 Together, these data indicate that under normal conditions, HNF4␣ activity is not affected by fatty acids, the endogenous ligands for HNF4␣.Loss-of-function mutations in human HNF4␣ are associated with maturity-onset diabetes of the young (MODY1), 6 characterized by autosomal dominant inheritance, early-onset diabetes, and pancreatic ␤-cell dys...

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“…Part of the explanation for this may be the lower production of cholic acid, the major suppressor of Cyp7a1 in mice. 15 A contributing factor may be that Cyp7a1 is regulated by a LXR-dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

Studies on the Cholesterol-Free Mouse

Heverin

Meaney

Brafman

et al. 2007

ATVB

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The changes in hepatic mRNA levels in combination with increased biliary and fecal excretion of neutral steroids, reduced tissue levels of plant sterols, increased plasma levels of triglyceride-rich VLDL, are consistent with a strong activation of LXR-targeted genes. The markedly increased fecal loss of neutral sterols may explain the fact that the Dhcr24-/- mice do not accumulate dietary cholesterol. The study illustrates the importance of the integrity of the cholesterol structure--presence of a double bond in the steroid side-chain is compatible with life but is associated with serious disturbances in sterol homeostasis.

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Cholic acid mediates negative feedback regulation of bile acid synthesis in mice

Cited by 107 publications

References 49 publications

Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine

Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine

Hepatic Hepatocyte Nuclear Factor 4α Is Essential for Maintaining Triglyceride and Cholesterol Homeostasis

Studies on the Cholesterol-Free Mouse

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