Bile Acid-Induced Liver Injury in Cholestasis
01 Jan 2017-pp 143-172
TL;DR: Bile acid biology, mechanism of cholestatic liver injury, and current and future bile acid-based therapeutics for cholESTasis are summarized.
Abstract: Bile acids are physiological detergent molecules synthesized from cholesterol exclusively in the hepatocytes. Bile acids play important roles in generating bile flow and facilitating intestinal nutrient absorption. Bile acids are endogenous ligands of nuclear receptors and cell surface G protein-coupled receptors, which regulate various biological processes including metabolism, immune response, and cell proliferation. Cholestasis is a pathological condition where bile flow out of the liver is reduced or blocked, leading to accumulation of bile acids, cell death, and inflammation in the liver. Chronic cholestasis leads to liver fibrosis, cirrhosis, failure, and carcinogenesis. During cholestasis, bile acid-activated signaling regulates bile acid detoxification mechanisms as well as cell survival and proliferation. The hydrophilic bile acid UDCA has been used as the primary cholestasis therapy for decades. Pharmacological agents targeting the bile acid receptors are being developed as novel therapeutics for cholestasis. This chapter summarizes bile acid biology, mechanism of cholestatic liver injury, and current and future bile acid-based therapeutics for cholestasis.
Citations
More filters
TL;DR: Betaine supplementation ameliorated hepatic injury as judged by decreased liver tissue histopathological alterations, a significant decrease in tissue markers of oxidative stress, and mitigation of serum biomarkers of hepatotoxicity.
86 citations
TL;DR: Evaluated pathologic effects of cholestasis-associated reproductive toxicity in male and female rats is restrictedly coupled with severe oxidative stress and mitochondrial impairment.
48 citations
TL;DR: Mitochondrial dysfunction and energy metabolism disturbances are introduced as a fundamental mechanism involved in the pathogenesis of bile acids-associated renal injury during cholestasis.
45 citations
TL;DR: It was found that NAC treatment significantly mitigated biomarkers of oxidative stress and alleviated tissue histopathological changes in cirrhotic rats, representing NAC as a potential protective agent with therapeutic capability in cholestasis and its associated complications.
Abstract: Cholestasis is a multifaceted clinical complication. Obstructive jaundice induced by bile duct ligation (BDL) is known as an animal model to investigate cholestasis and its associated complications...
30 citations
Cites background from "Bile Acid-Induced Liver Injury in C..."
...The liver is the primary organ influenced by cholestasis (Copple et al., 2010; Li & Chiang, 2017; Woolbright & Jaeschke, 2012)....
[...]
TL;DR: This review article comprehensively summarize the current knowledge regarding the roles and mechanisms of these hormones in liver regeneration and believes that these endocrinal hormones are important hepatic mitogens that strongly induce and accelerate hepatocyte proliferation (regeneration) by directly and indirectly triggering the activity of the involved signaling pathways, cytokines, growth factors, and transcription factors.
19 citations
Cites background from "Bile Acid-Induced Liver Injury in C..."
...Extrahepatic causes include choledocholithiasis, stricture of the common bile duct, hilar and distal cholangiocarcinoma, pancreatic cancer, and chronic pancreatitis.(28) Stiedl et al(29) elucidated whether GH resistance has a role in establishing liver fibrosis....
[...]
References
More filters
TL;DR: Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor, which demonstrates a mechanism by which bile acid transcriptionally regulate their biosynthesis and enterohepatic transport.
Abstract: Bile acids are essential for the solubilization and transport of dietary lipids and are the major products of cholesterol catabolism Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor When bound to bile acids, FXR repressed transcription of the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, and activated the gene encoding intestinal bile acid-binding protein, which is a candidate bile acid transporter These results demonstrate a mechanism by which bile acids transcriptionally regulate their biosynthesis and enterohepatic transport
2,414 citations
TL;DR: The potential exists for altering the bile acid pool by targeting key enzymes in the 7α/β-dehydroxylation pathway through the development of pharmaceuticals or sequestering bile acids biologically in probiotic bacteria, which may result in their effective removal from the host after excretion.
2,144 citations
TL;DR: Results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis and modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1.
Abstract: Bile acids regulate the transcription of genes that control cholesterol homeostasis through molecular mechanisms that are poorly understood. Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor. As ligands, these bile acids and their conjugates modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1. These results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis.
2,044 citations
TL;DR: Mise a jour: anatomopathologie, anomalies immunologiques et pathogenese, tests de laboratoire, manifestations cliniques et troubles associes, evolution, traitement.
Abstract: Mise a jour: anatomopathologie, anomalies immunologiques et pathogenese, tests de laboratoire, manifestations cliniques et troubles associes, evolution, traitement
1,939 citations
TL;DR: It is shown that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin, and indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators.
Abstract: While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.
1,852 citations