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Vol. 16 Issue S1

On the cover: The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver


  • Bile Acid Physiology Agostino Di Ciaula, Gabriella Garruti, Raquel Lunardi Baccetto, Emilio Molina-Molina, Leonilde Bonfrate, David Q.-H. Wang, Piero Portincasa Page 4-15

    The primary bile acids (BAs) are synthetized from colesterol in the liver, conjugated to glycine or taurine to increase their solubility, secreted into bile, concentrated in the gallbladder during fasting, and expelled in the intestine in response to dietary fat. As well as bio-transformed in the colon to the secondary BAs by the gut microbiota, reabsorbed in the ileum and colon back to the liver, and minimally lost in the feces. BAs in the intestine not only regulate the digestion and absorption of cholesterol, triglycerides, and fat-soluble vitamins, but also play a key role as signaling molecules in modulating epithelial cell proliferation, gene expression, and lipid and glucose metabolism by activating farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor-1 (GPBAR-1, also known as TGR5) in the liver, intestine, muscle and brown adipose tissue. Recent studies have revealed the metabolic pathways of FXR and GPBAR-1 involved in the biosynthesis and enterohepatic circulation of BAs and their functions as signaling molecules on lipid and glucose metabolism.

  • The Role of Bile Acids in Glucose Metabolism and Their Relation with Diabetes José A. González-Regueiro, Lidia Moreno-Castañeda, Misael Uribe, Norberto C. Chávez-Tapia Page 16-21

    Bile acids (BAs), the end products of cholesterol catabolism, are essential for the absorption of lipids and fat-soluble vitamins; but they have also emerged as novel signaling molecules that act as metabolic regulators. It has been well described that the enterohepatic circulation, a nuclear (FXR) and a cytoplasmic (TGR5/M-BAR) receptor aid in controlling hepatic bile acid synthesis. Modulating bile acid synthesis greatly impacts in metabolism, because these receptors also are implicated in glucose, lipid, and energy expenditure. Recent studies had revealed the way these receptors participate in regulating gluconeogenesis, peripheral insulin sensitivity, glycogen synthesis, glucagon like peptide 1 (GLP-1) and insulin secretion. Nowadays, it is demonstrated that enhancing bile acid signaling in the intestine contributes to the metabolic benefits of bile acid sequestrants and bariatric surgery on glucose homeostasis. This paper discusses the role of bile acid as regulators of glucose metabolism and their potential as therapeutic targets for diabetes.

  • The Role of the Gut Microbiota in Bile Acid Metabolism Oscar Ramirez-Pérez, Vania Cruz-Ramón, Paulina Chinchilla-López, Nahum Méndez-Sánchez Page 22-27

    The gut microbiota has been considered a cornerstone of maintaining the health status of its human host because it not only facilitates harvesting of nutrients and energy from ingested food, but also produces numerous metabolites that can regulate host metabolism. One such class of metabolites, the bile acids, are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. These bioconversions modulate the signaling properties of bile acids through the nuclear farnesoid X receptor and the G protein-coupled membrane receptor 5, which regulate diverse metabolic pathways in the host. In addition, bile acids can regulate gut microbial composition both directly and indirectly by activation of innate immune response genes in the small intestine. Therefore, host metabolism can be affected by both microbial modifications of bile acids, which leads to altered signaling via bile acid receptors, and by alterations in the composition of the microbiota. In this review, we mainly describe the interactions between bile acids and intestinal microbiota and their roles in regulating host metabolism, but we also examine the impact of bile acid composition in the gut on the intestinal microbiome and on host physiology.

  • Cholesterol and Lipoprotein Metabolism and Atherosclerosis: Recent Advances In reverse Cholesterol Transport Helen H. Wang, Gabriella Garruti, Min Liu, Piero Portincasa, David Q.-H. Wang Page 28-43

    Atherosclerosis is characterized by lipid accumulation, inflammatory response, cell death and fibrosis in the arterial wall, and is major pathological basis for ischemic coronary heart disease (CHD), which is the leading cause of morbidity and mortality in the USA and Europe. Intervention studies with statins have shown to reduce LDL cholesterol levels and subsequently the risk of developing CHD. However, not all the aggressive statin therapy could decrease the risk of developing CHD. Many clinical and epidemiological studies have clearly demonstrated that the HDL cholesterol is inversely associated with risk of CHD and is a critical and independent component of predicting its risk. Elucidations of HDL metabolism give rise to therapeutic targets with potential to raising plasma HDL cholesterol levels, thereby reducing the risk of developing CHD. The concept of reverse cholesterol transport is based on the hypothesis that HDL displays an cardioprotective function, which is a process involved in the removal of excess cholesterol that is accumulated in the peripheral tissues (e.g., macrophages in the aortae) by HDL, transporting it to the liver for excretion into the feces via the bile. In this review, we summarize the latest advances in the role of the lymphatic route in reverse cholesterol transport, as well as the biliary and the non-biliary pathways for removal of cholesterol from the body. These studies will greatly increase the likelihood of discovering new lipid-lowering drugs, which are more effective in the prevention and therapeutic intervention of CHD that is the major cause of human death and disability worldwide.

  • Bile Acids in the Treatment of Cardiometabolic Diseases Libor Vítek Page 44-53

    Bile acids (BA), for decades considered only to have fat-emulsifying functions in the gut lumen, have recently emerged as novel cardio-metabolic modulators. They have real endocrine effects, acting via multiple intracellular receptors in various organs and tissues. BA affect energy homeostasis through the modulation of glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor (FXR), as well as the cytoplasmic membrane G protein-coupled BA receptor TGR5 in a variety of tissues; although numerous other intracellular targets of BA are also in play.The roles of BA in the pathogenesis of diabetes, obesity, metabolic syndrome, and cardiovascular diseases are seriously being considered, and BA and their derivatives seem to represent novel potential therapeutics to treat these diseases of civilization.

  • Bile Acids in Cholestasis and its Treatment Juan Pablo Arab, Daniel Cabrera, Marco Arrese Page 54-58

    Bile acids (BA) are key molecules in generating bile flow, which is an essential function of the liver. In the last decades there have been great advances in the understanding of the role of a number of specific transport proteins present at the sinusoidal and canalicular membrane domains of hepatocytes and cholangiocytes in generating and maintaining bile flow. Also, a clearer understanding on how BA regulate their own synthesis and the expression and/or function of transporters has been reached. This new knowledge has helped to better delineate the pathophysiology of cholestasis and the adaptive responses of hepatocytes to cholestatic liver injury as well as of the mechanisms of injury of biliary epithelia. In this context, therapeutic approaches including new hydrophilic BA such as the conjugation-resistant nor- ursodeoxycholic acid, nuclear receptors (FXR, PPAR-alpha) agonists, FGF19 analogues, inhibitors of the apical sodium-dependent bile acid transporter [ASBT] and modulators of the inflammatory cascade triggered by BAs are being studied as novel treatments of cholestasis. In the present review we summarize recent experimental and clinical data on the role of BAs in cholestasis and its treatment.

  • Bile Acids in Nonalcoholic Fatty Liver Disease: New Concepts and Therapeutic Advances Vania Cruz-Ramón, Paulina Chinchilla-López, Oscar Ramirez-Pérez, Nahum Méndez-Sánchez Page 59-68

    Nonalcoholic liver disease (NAFLD) is a major emerging health burden that is a common cause of illness and death worldwide. NAFLD can progress into nonalcoholic steatohepatitis (NASH) which is a severe form of liver disease characterized by inflammation and fibrosis. Further progression leads to cirrhosis, which predisposes patients to hepatocellular carcinoma or liver failure. The mechanism of the progression from simple steatosis to NASH is unclear. However, there are theories and hypothesis which support the link between disruption of the bile acids homeostasis and the progression of this disorder. Previous studies have been demonstrated that alterations of these pathways can lead to dysregulation of energy balance and an increased of liver inflammation and fibrosis. In this review, we summarized the current knowledge of the interaction between BA and the process related to the development of NAFLD, besides, the potential targets for novel therapies.

  • Cross-Talk Between Bile Acids and Gastro-Intestinal and Thermogenic Hormones: Clues from Bariatric Surgery Gabriella Garruti, Agostino Di Ciaula, Helen H. Wang, David Q.-H. Wang, Piero Portincasa Page 69-83

    Obesity is rapidly increasing and has reached epidemic features worldwide. It's linked to insulin resistance, systemic low-grade inflammation and common pathogenic pathways with a number of comorbidities (including cancer), leading to high mortality rates. Besides change of lifestyles (diet and physical exercise) and pharmacological therapy, bariatric surgery is able to rapidly improve several metabolic and morphologic features associated with excessive fat storage, and currently represents an in vivo model to study the pathogenic mechanisms underlying obesity and obesity-related complications. Studies on obese subjects undergoing bariatric surgery find that the effects of surgery are not simply secondary to gastric mechanical restriction and malabsorption which induce body weight loss. In fact, some surgical procedures positively modify key pathways involving the intestine, bile acids, receptor signaling, gut microbiota, hormones and thermogenesis, leading to systemic metabolic changes. Furthermore, bariatric surgery represents a suitable model to evaluate the gene-environment interaction and some epigenetic mechanisms linking obesity and insulin resistance to metabolic diseases.

  • Bile Acids and Portal Hypertension Juan Pablo Arab, Francisco Barrera, Marco Arrese Page 84-87

    The recent discovery of bile acid (BA) receptors and a better delineation of the multiple roles of BAs in relevant biological processes have revamped BA research. The vasoactive actions of BAs were recognized more than three decades ago but the underlying mechanisms of the BA-induced vasorelaxation are now being clarified. Recent evidence shows that the BA receptors FXR and TGR5 are expressed in endothelial cells and may have important effects on both systemic and portal circulation. The availability of genetically engineered mice with ablation of BA receptors and the development of BA receptor agonists has allowed to explore the modulation of XR and, in a lesser extent, of TGR5 in the setting of portal hypertension (PHT) with promising results. In this review, we summarize recent data on how BA-dependent pathways influence several processes that impact in PHT and the preclinical data showing that pharmacological modulation of those pathways may hold promise in the treatment of PHT.

  • Bile Acids and Cancer: Direct and Environmental-Dependent Effects Agostino Di Ciaula, David Q.-H. Wang, Emilio Molina-Molina, Raquel Lunardi Baccetto, Giuseppe Calamita, Vincenzo O. Palmieri, Piero Portincasa Page 0-0

    Bile acids (BAs) regulate the absorption of fat-soluble vitamins, cholesterol and lipids but have also a key role as singalling molecules and in the modulation of epithelial cell proliferation, gene expression and metabolism. These homeostatic pathways, when disrupted, are able to promote local inflammation, systemic metabolic disorders and, ultimately, cancer. The effect of hydrophobic BAs, in particular, can be linked with cancer in several digestive (mainly oesophagus, stomach, liver, pancreas, biliary tract, colon) and extra-digestive organs (i.e. prostate, breast) through a complex series of mechanisms including direct oxidative stress with DNA damage, apoptosis, epigenetic factors regulating gene expression, reduced/increased expression of nuclear receptors (mainly farnesoid X receptor, FXR) and altered composition of gut microbiota, also acting as a common interface between environmental factors (including diet, lifestyle, exposure to toxics) and the molecular events promoting cancerogenesis. Primary prevention strategies (i.e. changes in dietary habits and lifestyle, reduced exposure to environmental toxics) mainly able to modulate gut microbiota and the epigenome, and the therapeutic use of hydrophilic BAs to counterbalance the negative effects of the more hydrophobic BAs might be, in the near future, part of useful tools for cancer prevention and management.

The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for the Study of the Liver and the Canadian Association for the Study of the Liver

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