Читать книгу Autoimmune Liver Disease - Группа авторов - Страница 28

Bile is a complex secretion that originates from hepatocytes and is modified distally by absorptive and secretory transport systems in the bile duct epithelium. Bile formation by the hepatocytes involves secretion of osmotically active inorganic and organic anions into the canalicular lumen, followed by passive water movement. Bile then enters the gallbladder where it is concentrated or is delivered directly to the bowel.

Bile comprises about 95% water in which are dissolved a number of endogenous constituents, including bile salts, bilirubin, phospholipid, cholesterol, amino acids, steroids, enzymes, porphyrins, vitamins, and heavy metals, as well as exogenous drugs, xenobiotics and environmental toxins [4]. Lipophilic constituents are in solution in mixed micelle composed of BAs, phospholipids, and cholesterol.

Bile is essential for several important functions:

 the excretion of potentially harmful exogenous lipophilic substances, as well as the excretion of endogenous substrates such as bilirubin and bile salts;

 the digestion and absorption of lipid in the gut by bile salts;

 cholesterol homeostasis, by facilitating intestinal cholesterol absorption and, on the other hand, promoting cholesterol elimination;

 the excretion of immunoglobulin A (IgA) and inflammatory cytokines, thus protecting the organism from enteric infections;

 signaling properties of the BAs in the liver and the intestine, which are mediated by nuclear BA receptors such as FXR, PXR and vitamin D receptor (VDR), as well as by membrane a5b1 integrin, epidermal growth factor receptor, and sphingosine‐1‐phosphate receptor 2.

Our understanding of cholestatic liver diseases has been profoundly advanced by the discovery of nuclear receptors for BA signaling and their role in hepatobiliary excretory function and the adaptive changes counteracting the liver injury caused by retained, potentially toxic, and proinflammatory BAs. Ligand‐activated nuclear receptors such as FXR control a broad range of metabolic processes, including hepatic BA transport and metabolism, lipid and glucose metabolism, drug disposition, as well as liver regeneration, inflammation, fibrosis, cell differentiation, and tumor formation. Moreover, FXR has anti‐inflammatory and immunomodulatory actions and controls intestinal integrity and permeability, as well as gut microbiota. Conversely, the gut microbiota metabolizes BAs, with formation of secondary BAs that, in turn, modulate BA signaling. Based on these broad physiologic effects in the liver and intestine, drugs targeting FXR and TGR5 therefore open important perspectives for pharmacotherapy of cholestatic and metabolic liver disorders, including the complications of liver cirrhosis such as portal hypertension and hepatocellular carcinoma (HCC).

In addition, BAs stimulate glucagon‐like peptide (GLP)‐1 production via TGR5 activation. GLP‐1 is known to promote insulin secretion and thus regulate glucose homeostasis. Because GLP‐1 mimetics and receptor agonists are currently under clinical development and have shown promise in improving glucose homeostasis in diabetes, BA‐based TGR5 agonists may be a potential therapeutic to stimulate GLP‐1 secretion in diabetic patients.