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/jci200216309

Cited by 42 publications

(67 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CYP8B1 is the only P-450 cytochrome identified that can 12a-hydroxylate several substrates (Andersson et al 1998. This has been further substantiated in Cyp8b1 knockout mice where CA production was lost due to complete deletion of the entire coding region of the gene (Li-Hawkins et al 2002). CA also performs a regulatory role in bile acid synthesis in the mouse via binding to the farnesoid X receptor, resulting in an increase of the inhibitory short heterodimer partner (SHP).…”

Section: Introductionmentioning

confidence: 93%

See 1 more Smart Citation

Human sterol 12α-hydroxylase (CYP8B1) is mainly expressed in hepatocytes in a homogenous pattern

Wang

Greene

Eriksson

et al. 2005

Histochem Cell Biol

Self Cite

View full text Add to dashboard Cite

The liver is the only organ where the complete synthesis of bile acids takes place. The present study was undertaken to investigate whether regional differences exist within the individual human hepatic lobuli regarding the pattern of expression of sterol 12alpha-hydroxylase (CYP8B1), a key enzyme in bile acid synthesis. A specific anti-human CYP8B1 peptide antiserum was developed and used for Western blotting and hepatic immunostaining of livers from various patients. CYP8B1 in human liver was expressed in the cytoplasm of hepatocytes with an even nonzonal distribution within the liver lobulus. Pericentral expression was confirmed for CYP2E1. A weak staining was noted in cholangiocytes and Kupffer cells. Previous studies on hepatic CYP27A1 and CYP7A1 in rats have shown a zonal expression, primarily in the pericentral region. Our studies indicate a different pattern for CYP8B1 expression in human liver, which was even rather than zonal.

show abstract

Section: Introductionmentioning

confidence: 93%

“…CA also performs a regulatory role in bile acid synthesis in the mouse via binding to the farnesoid X receptor, resulting in an increase of the inhibitory short heterodimer partner (SHP). The loss of CA releases the CYP7A1 gene from inhibition, leading to increased CYP7A1 mRNA and activity (Li-Hawkins et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Human sterol 12α-hydroxylase (CYP8B1) is mainly expressed in hepatocytes in a homogenous pattern

Wang

Greene

Eriksson

et al. 2005

Histochem Cell Biol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Male Cyp8b1 null mice on a mixed 129Sv/Ev; C57Bl/6 background as previously described and wild type littermates were used (Li-Hawkins et al 2002). In addition, Balb/cBy mice were utilized.…”

Section: Animals and Tissue Preparationmentioning

confidence: 99%

“…Cyp8b1 is the only P-450 cytochrome identiWed that can 12 -hydroxylate substrates Xowing through both the neutral and acidic pathways (Andersson et al 1998. No compensatory P-450 seems to exist since in Cyp8b1 null mice, with deletion of the entire coding region of the gene, the synthesis of CA was completely abolished (Li-Hawkins et al 2002). As a consequence of the loss of CA, the mice decreased their intestinal cholesterol absorption, increased the hepatic de novo cholesterol synthesis, and were protected from hyperlipidemia and gallstone formation (Murphy et al 2005;Wang et al 2006a, b).…”

Section: Introductionmentioning

confidence: 99%

“…Apart from its role in enhancing micellar formation in the small intestine, CA also performs a regulatory role within the bile acid synthesis in the mouse as a physiological ligand to the farnesoid X receptor (FXR), exerting regulation of many genes like short heterodimerizing partner (SHP) resulting in an increase of its mRNA. CA is important for the regulation of Cyp7a1 expression since it appears to be one of its physiological suppressants, operating via the FXR-SHP axis and the c-Jun N-terminal kinase pathway, leading to a tonic inhibition of Cyp7a1 mRNA, protein and activity (Gupta et al 2001;Li-Hawkins et al 2002).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential hepatocellular zonation pattern of cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) in the mouse

Wang

Olin

Rozell

et al. 2007

Histochem Cell Biol

Self Cite

View full text Add to dashboard Cite

The synthesis of primary bile acids is confined to the hepatocytes. This study aimed to evaluate the expression pattern within the liver architecture of the rate-limiting enzyme of the neutral pathway, cholesterol 7alpha-hydroxylase (Cyp7a1), and sterol 12alpha-hydroxylase (Cyp8b1), the enzyme necessary for the synthesis of cholic acid. Specific Cyp8b1 and Cyp7a1 peptide antiserums were used for immunohistochemical staining of livers from wild type and Cyp8b1 null mice, the latter instead expressing beta-galactosidase (beta-Gal) as a replacement reporter gene. Cyp8b1 was mainly expressed in the hepatocytes in a zonal pattern surrounding the central vein while the areas surrounding the portal zones showed much lower levels. The zonation was maintained in cholic acid-depleted mice using beta-Gal as a reporter protein. Cyp7a1 expression in wild type mice also showed a zonal distribution pattern, although less distinct, with a maximal expression within a 1-2 cell thick layer of hepatocytes surrounding the central vein. In Cyp8b1 null mice, a more intense staining was obtained, in accordance with the higher expression level of Cyp7a1, although the overall expression pattern was maintained. Our results in mice indicate possible differences in the regulation of the cellular zonation of Cyp7a1 and Cyp8b1. Also, cholic acid affects the set-point of Cyp7a1 expression but not its zonal distribution.

show abstract

Lipid‐activated nuclear receptors: from gene transcription to the control of cellular metabolism

Crestani

Mitro

Fabiani

2004

Euro J Lipid Sci & Tech

View full text Add to dashboard Cite

Lipid-activated nuclear receptors: from gene transcription to the control of cellular metabolism* Cellular homeostasis is maintained through a complicated network of signaling, transport and enzymatic events that take place in different compartments of the cell. The result of this composite network determines the cellular behavior in response to environmental challenges. Within this network, many cellular functions are regulated at the transcriptional level and consequently the comprehension of the molecular mechanisms of gene regulation is fundamental to fully understand how the cell reacts to environmental changes. Moreover, it offers an opportunity to find novel targets for the design of better strategies to improve healthy human nutrition and to treat metabolic diseases. In this framework, nuclear receptors have emerged as key regulators of many cellular functions in response to lipid action. In this review, we will discuss the new concepts on the biology of the recently "adopted" nuclear receptors sensing oxysterols (LXR), bile acids (FXR) and fatty acids (PPARs) and their function in the integrated regulation of lipid and glucose metabolism. We will also address the role played by other orphan nuclear receptors, such as FTF, SHP and HNF-4, acting in concert with these lipid-sensing nuclear receptors in the regulation of cellular metabolism.

show abstract

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

Cited by 42 publications

References 40 publications

Human sterol 12α-hydroxylase (CYP8B1) is mainly expressed in hepatocytes in a homogenous pattern

Human sterol 12α-hydroxylase (CYP8B1) is mainly expressed in hepatocytes in a homogenous pattern

Differential hepatocellular zonation pattern of cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) in the mouse

Lipid‐activated nuclear receptors: from gene transcription to the control of cellular metabolism

Contact Info

Product

Resources

About