Fibrates and cholestasis Ghonem, Nisanne S.; Assis, David N.; Boyer, James L.
Hepatology,
August 2015, Letnik:
62, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Cholestasis, including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), results from an impairment or disruption of bile production and causes intracellular retention of ...toxic bile constituents, including bile salts. If left untreated, cholestasis leads to liver fibrosis and cirrhosis, which eventually results in liver failure and the need for liver transplantation. Currently, the only therapeutic option available for these patients is ursodeoxycholic acid (UDCA), which slows the progression of PBC, particularly in stage I and II of the disease. However, some patients have an incomplete response to UDCA therapy, whereas other, more advanced cases often remain unresponsive. For PSC, UDCA therapy does not improve survival, and recommendations for its use remain controversial. These considerations emphasize the need for alternative therapies. Hepatic transporters, located along basolateral (sinusoidal) and apical (canalicular) membranes of hepatocytes, are integral determinants of bile formation and secretion. Nuclear receptors (NRs) are critically involved in the regulation of these hepatic transporters and are natural targets for therapy of cholestatic liver diseases. One of these NRs is peroxisome proliferator‐activated receptor alpha (PPARα), which plays a central role in maintaining cholesterol, lipid, and bile acid homeostasis by regulating genes responsible for bile acid synthesis and transport in humans, including cytochrome P450 (CYP) isoform 7A1 (CYP7A1), CYP27A1, CYP8B1, uridine 5'‐diphospho‐glucuronosyltransferase 1A1, 1A3, 1A4, 1A6, hydroxysteroid sulfotransferase enzyme 2A1, multidrug resistance protein 3, and apical sodium‐dependent bile salt transporter. Expression of many of these genes is altered in cholestatic liver diseases, but few have been extensively studied or had the mechanism of PPARα effect identified. In this review, we examine what is known about these mechanisms and consider the rationale for the use of PPARα ligand therapy, such as fenofibrate, in various cholestatic liver disorders. (Hepatology 2015;62:635–643
Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, ...followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.
Nonalcoholic fatty liver disease (NAFLD) is a major factor in the pathogenesis of type 2 diabetes (T2D) and nonalcoholic steatohepatitis (NASH). The mitochondrial protonophore 2,4 dinitrophenol (DNP) ...has beneficial effects on NAFLD, insulin resistance, and obesity in preclinical models but is too toxic for clinical use. We developed a controlled-release oral formulation of DNP, called CRMP (controlled-release mitochondrial protonophore), that produces mild hepatic mitochondrial uncoupling. In rat models, CRMP reduced hypertriglyceridemia, insulin resistance, hepatic steatosis, and diabetes. It also normalized plasma transaminase concentrations, ameliorated liver fibrosis, and improved hepatic protein synthetic function in a methionine/choline–deficient rat model of NASH. Chronic treatment with CRMP was not associated with any systemic toxicity. These data offer proof of concept that mild hepatic mitochondrial uncoupling may be a safe and effective therapy for the related epidemics of metabolic syndrome, T2D, and NASH.
Mechanisms of bile acid-induced (BA-induced) liver injury in cholestasis are controversial, limiting development of new therapies. We examined how BAs initiate liver injury using isolated liver cells ...from humans and mice and in-vivo mouse models. At pathophysiologic concentrations, BAs induced proinflammatory cytokine expression in mouse and human hepatocytes, but not in nonparenchymal cells or cholangiocytes. These hepatocyte-specific cytokines stimulated neutrophil chemotaxis. Inflammatory injury was mitigated in
mice treated with BA or after bile duct ligation, where less hepatic infiltration of neutrophils was detected. Neutrophils in periportal areas of livers from cholestatic patients also correlated with elevations in their serum aminotransferases. This liver-specific inflammatory response required BA entry into hepatocytes via basolateral transporter Ntcp. Pathophysiologic levels of BAs induced markers of ER stress and mitochondrial damage in mouse hepatocytes. Chemokine induction by BAs was reduced in hepatocytes from
mice, while liver injury was diminished both in conventional and hepatocyte-specific
mice, confirming a role for Tlr9 in BA-induced liver injury. These findings reveal potentially novel mechanisms whereby BAs elicit a hepatocyte-specific cytokine-induced inflammatory liver injury that involves innate immunity and point to likely novel pathways for treating cholestatic liver disease.
Activated by retinoids, metabolites of vitamin A, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) play important roles in a wide variety of biological processes, including ...embryo development, homeostasis, cell proliferation, differentiation and death. In this review, we summarized the functional roles of nuclear receptor RAR/RXR heterodimers in liver physiology. Specifically, RAR/RXR modulate the synthesis and metabolism of lipids and bile acids in hepatocytes, regulate cholesterol transport in macrophages, and repress fibrogenesis in hepatic stellate cells. We have also listed the specific genes that carry these functions and how RAR/RXR regulate their expression in liver cells, providing a mechanistic view of their roles in liver physiology. Meanwhile, we pointed out many questions regarding the detailed signaling of RAR/RXR in regulating the expression of liver genes, and hope future studies will address these issues.
•RAR/RXR stimulates expression of FGF21 and FGF19, leading to increased fatty acid oxidation and reduced levels of NEFA and TG.•RAR/RXR modulates bile acid homeostasis by regulating the expression of genes involved in bile acid synthesis and transport.•RAR/RXR represses liver fibrosis by blocking hepatic stellate cell activation and proliferation.•RAR/RXR accelerates lipid metabolism in macrophages by stimulating cholesterol transport.
Clinical disorders that impair bile flow result in retention of bile acids and cholestatic liver injury, characterized by parenchymal cell death, bile duct proliferation, liver inflammation and ...fibrosis. However, the pathogenic role of bile acids in the development of cholestatic liver injury remains incompletely understood. In this review, we summarize the current understanding of this process focusing on the experimental and clinical evidence for direct effects of bile acids on each major cellular component of the liver: hepatocytes, cholangiocytes, stellate cells and immune cells. During cholestasis bile acids accumulated in the liver, causing oxidative stress and mitochondrial injury in hepatocytes. The stressed hepatocytes respond by releasing inflammatory cytokines through activation of specific signaling pathways and transcription factors. The recruited neutrophils and other immune cells then cause parenchymal cell death. In addition, bile acids also stimulate the proliferation of cholangiocytes and stellate cells that are responsible for bile duct proliferation and liver fibrosis. This review explores the evidence for bile acid involvement in these phenomena. The role of bile acid receptors, TGR5, FXR and the sphingosine-1-phosphate receptor 2 and the inflammasome are also examined. We hope that better understanding of these pathologic effects will facilitate new strategies for treating cholestatic liver injury.
Division of Gastroenterology and Hepatology, Department of
Internal Medicine, Karl-Franzens University, School of Medicine,
Graz, Austria; and Department of Medicine and Liver
Center, Yale University ...School of Medicine, New Haven,
Connecticut
Trauner, Michael and
James
L. Boyer.
Bile Salt Transporters: Molecular Characterization, Function,
and Regulation. Physiol. Rev. 83: 633-671, 2003. Molecular
medicine has led to rapid advances in the characterization of
hepatobiliary transport systems that determine the uptake and excretion
of bile salts and other biliary constituents in the liver and
extrahepatic tissues. The bile salt pool undergoes an enterohepatic
circulation that is regulated by distinct bile salt transport proteins,
including the canalicular bile salt export pump BSEP (ABCB11), the
ileal Na + -dependent bile salt transporter ISBT (SLC10A2),
and the hepatic sinusoidal Na + - taurocholate cotransporting
polypeptide NTCP (SLC10A1). Other bile salt transporters include the
organic anion transporting polypeptides OATPs (SLC21A) and the
multidrug resistance-associated proteins 2 and 3 MRP2,3 (ABCC2,3).
Bile salt transporters are also present in cholangiocytes, the renal
proximal tubule, and the placenta. Expression of these transport
proteins is regulated by both transcriptional and posttranscriptional
events, with the former involving nuclear hormone receptors where bile
salts function as specific ligands. During bile secretory failure
(cholestasis), bile salt transport proteins undergo adaptive responses
that serve to protect the liver from bile salt retention and which
facilitate extrahepatic routes of bile salt excretion. This review is a
comprehensive summary of current knowledge of the molecular
characterization, function, and regulation of bile salt transporters in
normal physiology and in cholestatic liver disease and liver regeneration.
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