Differences in the Regulation of the Classical and the Alternative Pathway for Bile Acid Synthesis in Human Liver

Björkhem, Ingemar; Araya, Zufan; Rudling, Mats; Angelin, Bo; Einarsson, Curt; Wikvall, Kjell

doi:10.1074/jbc.m202343200

Cited by 59 publications

(29 citation statements)

References 27 publications

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“…It has been reported that there is a coordinate regulation of sterol 27-hydroxylase (CYP27A1) and cholesterol 7α-hydroxylase (CYP7A1) by bile acids in rats [160][161][162]. In humans, however, there appears to be little or no coordinate regulation of CYP7A1 and CYP27A1 at the transcriptional level, and human CYP27A1 is not subject to a negative feedback control by bile acids [163]. The results underline that marked species differences may exist in mechanisms for control of synthesis of bile acids and cholesterol homeostasis.…”

Section: Regulationmentioning

confidence: 96%

Enzymes in the Conversion of Cholesterol into Bile Acids

Norlin¹,

Wikvall

2007

CMM

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168

137

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This article aims to give an overview on the characterization, properties and regulation of enzymes, particularly the cytochrome (CYP) P450 enzymes, in the formation of bile acids from cholesterol. Bile acids are biologically active molecules that promote absorption of dietary lipids in the intestine and stimulate biliary excretion of cholesterol. Bile acids and oxysterols, formed from cholesterol, act as ligands to nuclear receptors regulating the expression of important genes in cholesterol homeostasis. Thus, the bioactivation of cholesterol into bile acids is crucial for regulation of cholesterol homeostasis. The primary human bile acids, cholic acid and chenodeoxycholic acid, are formed from cholesterol via several pathways involving many different enzymes. Many of these enzymes are cytochrome P450 (CYP) enzymes, introducing a hydroxyl group in the molecule. The "classic" pathway of bile acid formation starts with a 7alpha-hydroxylation of cholesterol by CYP7A1 in the liver. The "acidic" pathway starts with a hepatic or extrahepatic 27-hydroxylation by CYP27A1. There also exist some quantitatively minor pathways which may be of importance under certain conditions. Formation of cholic acid requires insertion of a 12alpha-hydroxyl group performed by CYP8B1. Oxysterols are precursors to bile acids, participate in cholesterol transport and are known to affect the expression of several genes in cholesterol homeostasis. Enzymes with capacity to form and metabolize oxysterols are present in liver and extrahepatic tissues. The enzymes, nuclear receptors and transcription factors involved in bile acid biosynthesis are potential pharmaceutical targets for the development of new drugs to control hypercholesterolemia and to prevent atherosclerosis and other diseases related to disturbed cholesterol homeostasis. The review will also discuss some inborn errors of bile acid biosynthesis and the recently acquired knowledge on the genetic defects underlying these diseases.

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Section: Regulationmentioning

confidence: 96%

Enzymes in the Conversion of Cholesterol into Bile Acids

Norlin¹,

Wikvall

2007

CMM

Self Cite

168

137

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“…In contrast, high-level expression of CYP7A1 increases the mRNA expression of LDL-R in liver cells and decreases the concentration of circulating LDL-cholesterol even in LDL-R-deficient mice [8]. In human, CYP7A1 expression is induced by its substrate cholesterol and inhibited by negative feedback from bile acid [9]. …”

Section: Introductionmentioning

confidence: 99%

The Effects of Jiang-Zhi-Ning and Its Main Components on Cholesterol Metabolism

Chen

Zhao

et al. 2012

Evidence-Based Complementary and Alternative Medicine

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To examine how Jiang-Zhi-Ning (JZN) regulates cholesterol metabolism and compare the role of its four main components. We established a beagle model of hyperlipidemia, fed with JZN extract and collected JZN-containing serum 0, 1, 2, 4, and 6 h later. Human liver cells Bel-7402 were stimulated with 10% JZN-containing serum as well as the four main components of JZN and Atorvastatin. The mRNA expression of LDL receptor (LDL-R), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoAR), cytochrome P450 7A1 (CYP7A1), and acetyl-Coenzyme A acetyltransferase 2 (ACAT2) was measured by real-time PCR. LDL-R surface expression and LDL-binding and internalization were examined by flow cytometry. The results showed that JZN-containing serum significantly increased the mRNA expression of LDL-R, HMG-CoAR, and CYP7A1 in Bel-7402 cells. All the four components significantly increased the mRNA and protein expression of LDL-R and HMG-CoAR and decreased the mRNA and protein expression of ACAT2 in Bel-7402 cells. Hyperinand chrysophanol also markedly increased the mRNA expression of CYP7A1. Stimulation with stilbene glycosidesignificantly increased the surface expression of LDL-R and the binding and internalization of LDL. In conclusion, JZN and its four components have close relationship with the process of cholesterol metabolism, emphasizing their promising application as new drug candidates in the treatment of hyperlipidemia.

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“…The metabolic basis behind this is unclear, but it is of interest to note that species differences have recently been described in the molecular regulation of bile acid synthesis. [57][58][59][60][61] Furthermore, there appear to be species differences in the plasma lipoprotein response to stimulation of bile acid synthesis in LDLR deficiency. 62 Thus, stimulation of cholesterol 7␣-hydroxylase by gene transfer, 63 GH treatment, 26 or interruption of bile acid intestinal uptake 45 lowers LDL cholesterol in LDLR-deficient knockout mice, whereas complete biliary diversion in homozygous FH does not lower plasma LDL.…”

Section: February 2004mentioning

confidence: 99%

Growth Hormone Induces Low-Density Lipoprotein Clearance but not Bile Acid Synthesis in Humans

Lind

Rudling

Ericsson

et al. 2004

ATVB

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Objective-Growth hormone (GH) induces hepatic low-density lipoprotein (LDL) receptors and lowers plasma cholesterol.We characterized the influence of GH treatment on plasma LDL clearance in normal humans and investigated the relative role of LDL receptor (LDLR) activity and stimulation of bile acid synthesis in subjects with different LDLR expression. Methods and Results-Plasma clearance of autologous 125 I-LDL was measured before and during 3 weeks of treatment with GH (0.1 IU/kg per day) in 9 healthy young males. Plasma LDL cholesterol was reduced by 13% and the fractional catabolic rate of LDL increased by 27%. More marked changes were seen in a patient with hypopituitarism substituted with GH (0.07 IU/kg per day) for 3 months. In a second study, GH dose-dependently reduced LDL cholesterol and increased Lp(a) levels in 3 groups of males: younger and elderly healthy subjects and heterozygous familial hypercholesterolemia (FH). No effect on bile acid synthesis measured by the plasma marker 7␣-hydroxy-4-cholesten-3-one was observed. In an LDLR-deficient FH homozygote, LDL cholesterol was not affected by GH. Conclusions-GH

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Differences in the Regulation of the Classical and the Alternative Pathway for Bile Acid Synthesis in Human Liver

Cited by 59 publications

References 27 publications

Enzymes in the Conversion of Cholesterol into Bile Acids

Enzymes in the Conversion of Cholesterol into Bile Acids

The Effects of Jiang-Zhi-Ning and Its Main Components on Cholesterol Metabolism

Growth Hormone Induces Low-Density Lipoprotein Clearance but not Bile Acid Synthesis in Humans

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