Bile Acids Synthesis
Mevalonate Pathway

Author: Gianpiero Pescarmona
Date: 13/07/2011

Description

Bile acids: regulation of synthesis, 2009

Bile acid synthesis.

Kegg

Cholesterol is converted to two primary bile acids in human liver, CA and CDCA (Key regulated enzymes, CYP7A1, CYP8B1, CYP27A1, and CYP7B1, in the pathways are indicated)

  • CYP7A1 initiates the classic (neutral) bile acid biosynthetic pathway in the liver.
  • CYP27A1 initiates the alternative (acidic) pathway in the liver and macrophages.

CA and CDCA are conjugated to glycine (G) and taurine (T).
BACS and BAT are two key enzymes involved in amino conjugation of bile acids.

In the intestine, conjugated CA and CDCA are deconjugated and then dehydroxylated at the 7α-position to the secondary bile acids DCA and LCA, respectively.

Classic

An inborn error of bile acid synthesis (3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency) presenting as malabsorption leading to rickets, 1999

Function

Regulation of bile acid synthesis by an ileal bile acid sensing system. Bile acids are synthesized from cholesterol in the liver. The rate-limiting enzyme in the pathway is cholesterol-7α-hydroxylase (Cyp7a1). Bile acids are secreted across the apical (canalicular) membrane into the bile canaliculus via the Bsep transporter). Bile is then released into the duodenum and flows through the intestinal lumen, where it emulsifies lipids. Lipids are primarily absorbed by enterocytes in the jejunum. The bile acids are transported through the apical Asbt transporter across into ileal enterocytes. Bile acids activate the farnesoid X receptor/retinoid X receptor (FXR/RXR), leading the induction of Fgf15 and Ostαβ. The bile acids are then released into the portal circulation via basolateral Ostα/β and reabsorbed by the hepatic basolateral transporter, Ntcp. FGF15 binds to the FGF4 receptor, leading to the repression of Cyp7a1 expression and reduced bile acid synthesis.
Deletion of the ileal basolateral bile acid transporter identifies the cellular sentinels that regulate the bile acid pool, 2008

Comments
2012-02-22T21:51:16 - Matteo Martini

Bile acids endocrine functions

Bile acids, besides their roles in lipid absorption and cholesterol homeostasis, act also as signaling molecules with systemic effects.

Their endocrine and paracrine functions are principally mediated by nuclear receptors, such as the FXR (farnesoid X receptor), and by the recently discovered G-protein coupled TGR5 (Gpbar-1).

FXR TGR5

for integration in the cholesterol metabolism view Cholesterol Serum Influx/Efflux

Bile acids homeostasis: activation of FXR in the liver promotes several pathways (like the upregulation of the small heterodimer partner-1, SHP) that lead to the suppression of the Cyp7a1 and of the Cyp8b1, while the efflux from the hepatocyte is increased. TGR5 signaling may also be involved.

Lipid homeostasis: SREB-1c mediated lipogenesis is inhibited by FXR and SHP Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c, 2004. Lipoprotein lipase is activated by the expression of apolipoprotein CII and the repression of ApoCIII. Expression of PPARα and activation of pyruvate dehydrogenase kinase-4 (PDK4) increase the fatty acid oxidation.

Glucose homeostasis: Bile acids and signal transduction: role in glucose homeostasis, 2008 FXR represses gluconeogenic genes and increases glycogen synthesis Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice

Energy expenditure: Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation, 2006 This work shows that bile acids in mice brown adypocite but also in human skeletal muscle increase energy expenditure by promoting the cAMP-dependent iodothyronine deiodinase type 2 (D2). However this model might not be readily translatable to human: analyzing type 2 diabetic patients, healthy controls and patient with liver cirrhosis no significant correlation between plasma BA and energy expenditure was found Plasma bile acids are not associated with energy metabolism in humans, 2010

Further effects: TGR5 is highly expressed in CD14-positive monocytes, alveolar macrophages and Kupffer cells and bile acids have been recognized to have immunomodulatory functions Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-alpha production by monocytes, 1992 Bile acids induce monocyte differentiation toward IL-12 hypo-producing dendritic cells via a TGR5-dependent pathway, 2012

FXR has been shown to induce genes involved in enteroprotection and inhibit bacterial overgrowth Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor, 2006 and to be involved in liver regeneration Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration, 2006

also VDR binds BAs acting as a bile acid sensor in the intestine. See Red Meat and Colorectal Cancer

BAs exert also effects on the cardiovascular system Bile acids regulate cardiovascular function, 2011 and this could be important in end-stage liver disease, obstructive jaundice and other conditions in which elevated serum BAs can alter vascular parameters.

FXR is also tought to be involved in the pathophysiology of hepatobiliary and gastrointestinal diseases Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease, 2010

Though not yet investigated in its implications a neuronal modulation by chenodeoxycholate has been highlighted in hypothalamic network The bile steroid chenodeoxycholate is a potent antagonist at NMDA and GABA receptors, 2012 .

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