Mini-Symposium
Bile salts and cholestasis

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Abstract

Bile salts have a crucial role in hepatobiliary and intestinal homeostasis and digestion. Primary bile salts are synthesized by the liver from cholesterol, and may be modified by the intestinal flora to form secondary and tertiary bile salts. Bile salts are efficiently reabsorbed from the intestinal lumen to undergo enterohepatic circulation. In addition to their function as a surfactant involved in the absorption of dietary lipids and fat-soluble vitamins bile salts are potent signaling molecules in both the liver and intestine.

Under physiological conditions the bile salt pool is tightly regulated, but the adaptive capacity may fall short under cholestatic conditions. Elevated serum and tissue levels of potentially toxic hydrophobic bile salts during cholestasis may cause mitochondrial damage, apoptosis or necrosis in susceptible cell types.

Therapeutic nontoxic bile salts may restore impaired hepatobiliary secretion in cholestatic disorders. The hydrophilic bile salt ursodeoxycholate is today regarded as the effective standard treatment of primary biliary cirrhosis and intrahepatic cholestasis of pregnancy, and is implicated for use in various other cholestatic conditions. Novel therapeutic bile salts that are currently under evaluation may also prove valuable in the treatment of these diseases.

Introduction

Bile salt synthesis, secretion and recycling represent crucial functions of the liver, the central organ for the maintenance of metabolic homeostasis. Bile salts form two thirds of organic compounds in mammalian bile and are continuously recycled in the body by undergoing a highly efficient enterohepatic circulation. In the small intestine, the amphipathic molecules function as micellar solubilizers, mediating the intestinal uptake of dietary fats. In addition, bile salts represent potent signaling molecules in liver and intestine: in the small intestine, they strengthen the defence against microbes by farnesoid X receptor (FXR)-dependent mechanisms and modulate hepatobiliary bile formation by FXR-controlled ileal release of the peptide hormone fibroblast growth factor 19 (FGF19) [1], [2]. In the liver, bile salts directly modulate their hepatocellular uptake, synthesis and biliary secretion at both the transcriptional level via activation of nuclear receptors and at the posttranslational level via modulation of cytosolic signaling cascades [3], [4], [5].

The adaptive functions of bile salts may decompensate under the pathological condition of bile secretory impairment. Bile salts are suspected to be the main causative agents of cellular damage to hepatocytes and cholangiocytes during cholestasis [6].

The dual nature of bile salts, with their various biological functions on one hand and their potentially cytotoxic effects when accumulating in cholestasis on the other hand, are the focus of this review. Therapeutic effects of bile salts like ursodeoxycholate in the treatment of several of these cholestatic diseases are also addressed.

Section snippets

Evolutionary perspective on bile salts

The chemical structure of bile salts differs markedly between vertebrate species, although all are variants of the same type of molecule. Among the different animal orders, but less so among families, genera and species, evolutionary processes have selected a range of distinct bile salts. ‘The end products of bile salt biosynthesis in lower vertebrates are the precursors of end products of bile salt biosynthesis in higher vertebrates’[7]. New bile salts are discovered regularly as mass

Synthesis and chemical properties

Primary bile salts – cholate (C) and cheonodeoxycholate (CDC) in humans – are synthesized by hepatocytes via enzymatic modification of cholesterol, adding hydroxyl groups and oxidizing the side chain. The thus formed bile salt is an amphipathic molecule, much more hydrophilic than cholesterol, which empowers it to efficiently form micelles [3], [10]. These characteristics are necessary for the physiological function of bile salts during fat uptake from the intestine but also make them

Induction of bile flow

Bile salts are the major osmotic driving force for bile formation. Active secretion of bile salts against a steep concentration gradient across the apical hepatocyte membrane leads to passive water movement into bile, forming the bile salt-dependent fraction of bile flow.

Detoxification

Liver and small intestine are the main sites of detoxification in the body, and bile is the primary excretory route for substances such as bilirubin, cholesterol and waste products. Bile salts help solubilise lipophilic

Pathological effects of bile salts

Bile salts are potentially toxic to living cells when present at supraphysiologic levels. At low micromolar concentrations, unconjugated more than conjugated hydrophobic bile salts such as LC, CDC, or DC can cause damage particularly of mitochondria, without affecting integrity of plasma membranes. At high micromolar and millimolar concentrations they may even dissolve plasma membranes [81], [82]. The more hydrophilic conjugated bile salts like GUDC generally only yield toxic effects at doses

Ursodeoxycholate (UDC)

Extensive experimental evidence of the past 25 years [105] indicates that UDC improves impaired hepatocellular [106] as well as cholangiocellular [107] secretion by mainly posttranscriptional mechanisms as reviewed previously [14], [108], [109], [110]. In cholestatic hepatocytes, Ca2+/cPKCα/PKA-dependent [14], [106], [111], [112] or possibly MAPK-dependent [67] targeting of apical transporters such as the bile salt and conjugate export pumps, Bsep and Mrp2, may contribute to the anticholestatic

Conclusion

Fifty years ago bile salts were regarded as single-purposed detergents that were only produced to aid fat digestion. As for so many examples from the medical field new techniques unveiled numerous additional functions of bile salts, which enabled the development of clinical applications of these multifaceted molecules. Bile salt therapy is currently the pillar of treatment of several chronic cholestatic diseases, and while a better understanding of the potentially harmful properties of bile

Conflict of interest statement

Ulrich Beuers has received lecture fees from the Falk Foundation, Gilead, Roche, Schering-Plough and Zambon. Lucas Maillette de Buy Wenniger has nothing to disclose.

List of abbreviations

ASBT, apical sodium-dependent bile salt cotransporter; BSEP, bile salt and conjugate export pump; C, cholate; CCA, cholangiocarcinoma; CDC , chenodeoxycholate; DC, deoxycholate; 6-ECDC, 6-ethylchenodeoxycholate; ER, endoplasmic reticulum; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; MAPK, mitogen-activated protein

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