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With the rapid increase in the prevalence rate of nonalcoholic fatty liver disease (NAFLD), new treatment methods are needed to prevent disease progression to liver fibrosis, liver cirrhosis, and liver cancer. Although great efforts have been made to clarify the pathological mechanisms of NAFLD disease progression, there are still no effective treatment methods at present. Bile acids (BAs) regulate systemic metabolism by activating nuclear receptors and G protein-coupled receptors and have been identified as important signaling molecules involved in lipid, glucose, and energy metabolism. Dysregulation of BA homeostasis is associated with the severity of NAFLD. This article summarizes the important ligands in BA metabolism and their role in the progression of NAFLD, in order to provide a basis for the treatment of NAFLD by targeting BA messengers.
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Intestinal microbiota plays an important role in maintaining liver metabolic homeostasis and affects the development and progression of hepatocellular carcinoma by participating in bile acid metabolism. Gut-liver axis plays an important role in the pathogenesis of liver diseases， and it might be one of the effective methods to prevent the progression of hepatocellular carcinoma by correcting intestinal ecological imbalance to restore normal bile acid level. This article summarizes the mechanism of bile acid receptor affecting hepatocellular carcinoma and the latest therapeutic targets， in order to provide a reference for the early prevention and treatment of hepatocellular carcinoma.
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Bile acids are synthesized and catabolized by the liver, and many factors can lead to disorders in the production, secretion, and reabsorption of bile acids, thereby causing abnormal bile acid metabolism in vivo . Common predisposing factors include hepatitis, viruses, alcohol, drugs, biliary obstruction, and inheritance. It has been reported that abnormal bile acid metabolism is associated with transporter gene mutation, and in-depth studies have been conducted in China and globally. This article reviews the mechanism of abnormal bile acid metabolism caused by gene mutations and related research advances, so as to provide a new basis and new ideas for the diagnosis and treatment of such diseases.
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The intestinal microbiota refers to the microbial group that exists in the intestine, and its composition disorder may affect human health. Many studies have found that intestinal microbiota and their metabolites may be closely related to the pathologies of Alzheimer′s disease (AD) through the gut-brain axis. This article will review the roles and possible mechanisms of lipopolysaccharide, functional bacterial amyloid proteins and bile acids, which are common metabolites of intestinal microbiota, in the pathogenesis of AD, and provide valuable information for exploring the pathogenesis of AD.
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Objective:To investigate the significance of serum glycocholic acid (CG), total bile acid (TBA), and glucagon-like peptide-1 (GLP-1) in the transformation of fatty liver to liver cancer and their relationship with the body′s glucose and lipid metabolism.Methods:From May 2018 to August 2020, 96 patients with fatty liver (fatty liver group), 96 patients with liver cirrhosis (cirrhosis group) and 96 patients with liver cancer (liver cancer group) admitted to Jintang Hospital of West China Hospital of Sichuan University were selected. Ninety-six healthy physical examination patients were selected during the same period as the normal control group. Compared the general information, serum CG, TBA, GLP-1, glycosylated hemoglobin (HbA 1c), triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) levels of each group. The correlation between serum CG, TBA, GLP-1 levels and the body′s glucose and lipid metabolism indicators were analyzed by Pearson correlation. The correlation between serum CG, TBA, GLP-1 and clinical stage were analyzed. Results:The levels of serum CG, TBA, GLP-1, and HbA 1c in the fatty liver group, cirrhosis group, liver cancer group were higher than those in the normal control group: (3.57 ± 1.06), (22.17 ± 8.44),(31.44 ± 9.65) mg/L vs. (1.26 ± 0.78) mg/L; (5.94 ± 1.26), (12.34 ± 4.02), (20.65 ± 5.17) μmol/L vs. (2.87 ± 0.59) μmol/L; (8.34 ± 1.55), (11.69 ± 3.26), (17.84 ± 2.78) pmol/L vs. (6.68 ± 1.24) pmol/L; (5.52 ± 0.31)%, (5.89 ± 0.27)%, (6.11 ± 0.23)% vs. (5.11 ± 0.36)%, and with the progression of the disease, the levels showed a rising trend, and the differences were statistically significant ( P<0.05). The levels of TG, TC, HDL-C, LDL-C in the cirrhosis group and liver cancer group were lower than those in the normal control group and fatty liver group, the differences were statistically significant ( P<0.05). The results of correlation analysis showed that serum CG, TBA, GLP-1 were positively correlated with HbA 1c ( P<0.05), and serum CG, TBA, GLP-1 were negatively correlated with TG, TC, HDL-C, and LDL-C ( P<0.05). With the increase of clinical stage, serum CG and TBA levels showed an increasing trend ( P<0.05). Conclusions:With the transformation of fatty liver to liver cancer, serum CG, TBA, and GLP-1 levels increase, and the change trend is closely related to the body′s glucose and lipid metabolism, which can provide a reference for the clinical improvement of fatty liver outcome evaluation mechanism.
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Primary biliary cholangitis (PBC) is an autoimmune disease. Although PBC has the features of autoimmune disease, it has poor response to immunosuppressants and good response to the drugs participating in bile acid metabolism, such as ursodeoxycholic acid. Studies have shown that the bicarbonate secretion of biliary epithelial cells is impaired in PBC patients, and bile acid not blocked by HCO3- umbrella enters biliary epithelial cells and mediates their damage and apoptosis, leading to the expression of autoantibodies in apoptotic cells and immunologic injury. In order to explore the role of HCO3- umbrella secreted by biliary epithelial cells in the pathogenesis of PBC, this article briefly introduces the physiological function and production mechanism of HCO3- umbrella and the influencing factors for HCO3- secretion, and it is pointed out that reduced HCO3- secretion may be a key link in the pathogenesis of PBC and a potential therapeutic target.
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Bile acid metabolism, gut microbiota, and bile acid receptors are involved in the development and progression of hepatocellular carcinoma (HCC). There are substantial increases in the levels of some bile acids, such as glycocholic acid, taurocholic acid, and taurochenodeoxycholic acid, in the liver tissue of HCC mice and the serum and feces of HCC patients. Bile acid metabolism due to the imbalance of the abundance of bacteria producing bile salt hydrolases and Clostridium in the intestine and the change in immune microenvironment may also promote the development of HCC. Moreover, some bile acid receptors, such as farnesoid X receptor, G protein-coupled bile acid receptor 1, pregnane X receptor, constitutive androstane receptor, and sphingosine-1-phosphate receptor 2, have been shown to participate in the development and progression of HCC through various pathways. Each link of bile acid metabolism plays a different role in the progression of HCC, and a systematic elaboration of the interaction between these links may help to deepen the understanding of the pathogenesis of HCC and develop the biological targets for early diagnosis, prognosis prediction, and precise treatment.
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Bile acids (BAs) are produced in the liver and are the final product of cholesterol catabolism, with a wide range of biological effects. This article reviews the research advances in the synthesis, transport, and metabolism of BAs and the role of BAs in regulating hepatocytes and immunity via enterohepatic circulation, as well as the current research on traditional Chinese medicine in the regulation of BAs, in order to further understand the mechanism of action of BAs in affecting intestinal flora and liver function, expand the knowledge of its regulatory mechanism, explore the mechanism of action of traditional Chinese medicine and related pathways in regulating BAs, and provide new ideas for the prevention and treatment of liver-related systemic diseases by regulating BAs.
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Cholestatic liver diseases (CHD) refers to a kind of liver disease in which accumulation of excessive bile due to various causes from inside and outside of the liver blocks the formation, secretion and excretion of bile, and thereby induce the normal bile flow unable to enter the duodenum. During the occurrence and development of CHD, intestinal microflora plays an important role in regulating bile acid metabolism, and immune response. In addition, CHD affects the composition, abundance and function of intestinal microflora, which in turn affects the synthesis and metabolism of bile acids. Hence, bile acids being an important signaling molecule for the occurrence and development of CHD plays role in the pathophysiological processes through bile acid transporters and nuclear receptors, such as farnesoid receptors. This paper briefly introduces the relationship between intestinal microecology and cholestatic liver disease based on the interrelationship among bile acid, intestinal flora and cholestatic liver disease, with a view to provide assistance in the treatment of cholestatic liver disease.
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Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and non-alcoholic fatty liver disease. Primary bile acids are synthesized in hepatocytes and are transformed to secondary bile acids in the intestine by gut bacteria. Bile acids are nutrient sensors and metabolic integrators that regulate lipid, glucose, and energy homeostasis by activating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5. Bile acids control gut bacteria overgrowth, species population, and protect the integrity of the intestinal barrier. Gut bacteria, in turn, control circulating bile acid composition and pool size. Dysregulation of bile acid homeostasis and dysbiosis causes diabetes and obesity. Targeting bile acid signaling and the gut microbiome have therapeutic potential for treating diabetes, obesity, and non-alcoholic fatty liver disease.
Subject(s)
Bacteria , Bile Acids and Salts , Bile , Cardiovascular Diseases , Dysbiosis , Gastrointestinal Microbiome , Glucose , Hepatocytes , Homeostasis , Intestines , Membranes , Non-alcoholic Fatty Liver Disease , Obesity , Receptors, Cytoplasmic and Nuclear , Receptors, G-Protein-CoupledABSTRACT
Normal bile formation, secretion, and excretion are important physiological processes in human body. Bile plays an important role in promoting lipid digestion and absorption, eliminating metabolic waste, and regulating cholesterol metabolism. Disorders in bile formation, secretion, or excretion due to various causes may lead to acute or chronic cholestatic diseases. A deep understanding of the role of bile formation, secretion, and excretion and the pathogenesis of cholestasis is of great significance in the research on cholestatic liver diseases and clinical practice.
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Cholestasis refers to a pathological state of disorders in the formation, secretion, and excretion of bile flow, and liver fibrosis is a process of tissue repair induced by liver injury. Cholestatic liver disease is a chronic liver disease caused by cholestasis, progressive bile duct injury, and persistent intrahepatic inflammation, and it may cause cholangiocyte and hepatocyte injury, which will gradually progress to liver fibrosis. With reference to the current research advances, this article reviews the pathogenesis of cholestasis-induced liver fibrosis and the strategies for blockade.
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Objective To observe the changes of glycocholic acid (CG) and evaluate the diagnostic value of CG combined with total bile acid (TBA) and leucine aminopeptidase (LAP) in various liver diseases.Methods From October 2016 to March 2017,210 serum samples of healthy people,asymptomatic hepatitis B virus (HBV) infected,hepatitis,biliary obstruction,hepatocirrhosis and primary hepatocellular carcinoma patients were collected.CG and LAP were detected by corresponding kits,and liver function,coagulation function and other indicators of patients were collected and analyzed statistically.Results The serum level of CG were elevated in the 4 liver disease groups and differed statistically from the normal group or the asymptomatic HBV infected group.CG level was positively correlated with LAP (r =0.380,P ＜ 0.01).In liver function indexes,CG was correlated with total bilirubin (TB),direct bilirubin (DB),TBA and alkaline phosphatase (AKP).At the same time,CG was correlated with fibrinogen(Fib),thrombin time(TT).LAP and TBA were introduced into regression equation Y =-0.835 + 0.157X1 +0.312X2 (X1:LAP,X2:TBA,R2 =0.685) as final variables in multivariate linear regression to analyse the influencing factors of CG.Receiver operator characteristic (ROC) curve analysis showed that CG had the strongest ability to diagnose liver diseases in combination with LAP.Conclusions The change of CG level is of great significance in all kinds of liver diseases.The combination of LAP has the strongest ability to diagnose liver diseases.
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Background: Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene resulting in a decreased synthesis of bile acids. An early diagnosis and treatment would reduce the longterm complications observed in this disease. Aim: To identify and hierarchize initial clinical signs of CTX to establish an early diagnostic suspicion index. Material and Methods: Clinical information was collected from 387 patients diagnosed with CTX, published in MEDLINE between 1968 and 2016. Clinical manifestations were identified, determining their prevalence and age of onset. Sensitivity, specificity and the positive Likelihood ratio (LR+) was calculated for each clinical sign evaluated. Results: The average ages for early symptoms' onset and CTX diagnosis were 13.3 ± 10.6 years and 34.6 ± 12.6 years respectively. The early clinical signs and their respective LR+ were: juvenile cataracts (143), epilepsy (81), chronic diarrhea (15.6) and psychomotor development delay (3.4). The presence of consanguinity among parents resulted in a LR+ of 31. The combination of two early signs increased the post-test probability to 30%. If the early diagnostic criteria would have been applied in three Chilean patients with diagnosis of CTX, their disease would have been diagnosed from 12 to 25 years earlier. Conclusions: The use of a hierarchical system of predictive clinical signs allows an early screening of CTX, which may avoid the natural progression of the disease using an appropriate treatment.
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Humans , Male , Female , Xanthomatosis, Cerebrotendinous/diagnosis , Xanthomatosis, Cerebrotendinous/pathology , Clinical Trials as Topic , Age of Onset , Disease Progression , Early DiagnosisABSTRACT
Although genetic background is known to contribute to colon carcinogenesis, the exact etiology of the disease remains elusive. The organ’s extensive interaction with microbes necessitated research on the role of microbiota on development of colon cancer. In this review, we summarized the defense mechanism of colon from foreign organism, and germ-free animal models that have been employed to elucidate microbial effect. We also comprehensively discussed the metabolic property of microbiota such as butyrate production, facilitation of heme toxicity, bile acid transformation, and nitrate reduction that has been shown to contribute to the development of the tumor. Finally, up-to-date subjects such as the effect of age and gender on microbiota are briefly discussed.
Subject(s)
Bile , Bile Acids and Salts , Butyrates , Butyric Acid , Carcinogenesis , Colon , Colonic Neoplasms , Genetic Background , Heme , Microbiota , Models, AnimalABSTRACT
Oxysterol 7α-hydroxylase deficiency is a very rare liver disease categorized as inborn errors of bile acid synthesis, caused by CYP7B1 mutations. As it may cause rapid progression to end-stage liver disease even in early infancy, a high index of suspicion is required to prevent fatal outcomes. We describe the case of a 3-month-old boy with progressive cholestatic hepatitis and severe hepatic fibrosis. After excluding other etiologies for his early liver failure, we found that he had profuse urinary excretion of 3β-monohydroxy-Δ5-bile acid derivatives by gas chromatography/mass spectrometry analysis with dried urine spots on filter paper. He was confirmed to have a compound heterozygous mutation (p.Arg388Ter and p.Tyr469IlefsX5) of the CYP7B1 gene. After undergoing liver transplantation (LT) from his mother at 4 months of age, his deteriorated liver function completely normalized, and he had normal growth and development until the current follow-up at 33 months of age. We report the first Korean case of oxysterol 7α-hydroxylase deficiency in the youngest infant reported to undergo successful living donor LT to date.
Subject(s)
Humans , Infant , Male , Bile , Bile Acids and Salts , Fatal Outcome , Fibrosis , Follow-Up Studies , Growth and Development , Hepatitis , Liver , Liver Diseases , Liver Failure , Liver Transplantation , Living Donors , Mothers , Spectrum AnalysisABSTRACT
Objective To study the diagnostic value of hepatobiliary imaging at 6 h post-injection of 99 Tcm-diethyl iminodiacetic acid ( EHIDA) ( HI-6) combined with serum gamma-glutamyltransferase (γ-GT)/total bile acid ( TBA) ratio ( combined diagnosis) in children with congenital extrahepatic biliary atre-sia (CEBA). Methods Clinical data of 194 pediatric patients (118 males, 76 females, mean 70.9 d) with jaundice from May 2013 to March 2017 were retrospectively analyzed. All patients underwent surgery. According to the operation and pathologic diagnosis, patients were divided into CEBA group ( 113 cases) , infant hepatitis syndrome ( IHS) group ( 81 cases) . Serumγ-GT, TBA and the ratio ofγ-GT/TBA of the 2 groups were compared. Receiver operating characteristic ( ROC) curves were drawn to determine threshold values of the 3 parameters for diagnosis of CEBA. Patients also underwent 99 Tcm-EHIDA hepatobiliary dy-namic imaging. The diagnostic efficacies of HI-6, γ-GT, γ-GT/TBA ratio, and combined diagnosis were compared. Two-sample t test and χ2 test were used to analyze the data. Results There were significant differences in γ-GT/TBA ratio,γ-GT and TBA content between the 2 groups (t values:8.217, 9.298 and 2.426, all P<0.05). The serumγ-GT andγ-GT/TBA ratio had high diagnostic accuracies (area under ROC curve ( AUC):0.884 and 0.863) . The sensitivity, specificity, accuracy and positive predictive value of HI-6 in the diagnosis of CEBA were 91.15％(103/113), 39.51％(32/81), 69.59％(135/194) and 67.76％(103/152);the parameters of γ-GT were 69.91％(79/113), 93.83％(76/81), 79.90％(155/194) and 94.05％(79/84);and those ofγ-GT/TBA ratio were 71.68％(81/113), 92.59％(75/81), 80.41％(156/194) and 93.10％(81/87). The sensitivity of HI-6 was significantly higher than that of γ-GT and GGT/TBA ratio (χ2 values:16.256 and 14.154, both P<0.05) , but the specificity, accuracy and positive predic-tive value were significantly lower than those ofγ-GT/TBA ratio (χ2 values:50.899, 6.062 and 20.054, all P<0.05). The specificity, accuracy and positive predictive value of the combined diagnosis were 95.06％(77/81), 92.78％(180/194) and 96.26％(103/107) respectively, which were significantly higher than those of HI-6 (χ2 values:56.786, 34.168 and 31.335, all P<0.05) . Conclusions HI-6 combined withγ-GT/TBA ratio can significantly improve the diagnostic specificity and accuracy for CEBA. This method is more time-saving, simple and reliable, and has important clinical value.
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Cholestasis refers to damage of bile formation or flow at the level of hepatocytes and/or bile duct cells,resulting in the inability of bile to excrete normally into the duodenum and deposit in the liver.Excessive bile acids and bilirubin cause liver cell damage and hepatic fibrosis until liver failure.Therefore,the specific mechanism for the occurrence and development of cholestasis is of great significance for the treatment of the disease and the prognosis of the patient.
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Background: The incidence of inflammatory bowel disease (IBD) is increasing in recent years, and the etiology and pathogenesis of IBD remain unclear.Studies showed that disorder of bile acid metabolism plays an important role in the pathological process of experimental colitis.However, serum bile acid profile in IBD patients has not been reported.Aims: To investigate the changes of serum bile acid profile in patients with IBD.Methods: Seven healthy controls, 15 patients with ulcerative colitis (UC) and 16 patients with Crohn's disease (CD) at Shanghai Xin Hua Hospital were enrolled.High-performance liquid chromatography-mass spectrometry was used to determine serum bile acid profile.Results: No significant differences in serum concentrations of primary bile acid cholic acid (CA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), taurocholic acid (TCA), glycochenodeoxycholic acid (GCDCA) were found between UC or CD and controls (P>0.05).Compared with controls, serum concentration of secondary bile acid deoxycholic acid (DCA) in UC patients was significantly decreased (P<0.05), glycodeoxycholic acid (GDCA), taurodeoxycholic acid (TDCA) in CD patients were significantly decreased (P<0.05), serum concentration of lithocholic acid (LCA) in UC and CD patients was significantly decreased (P<0.05).Conclusions: The serum bile acid profile in IBD patients is significantly changed, which suggests that it may be involved in the pathological process of IBD.
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Objective To investigate the correlation between serum total bile acid level and coronary atherosclerosis. Methods The clinical data of 1408 patients who had underwent coronary angiography were retrospectively analyzed. The patients were divided into coronary atherosclerosis group (stenosis ≥ 50%, 681 cases) and coronary normal group (stenosis 0.05). The rate of smoking, rate of hypertension, rate of diabetes, age, body mass index (BMI), creatinine, fasting plasma glucose, total bile acid and low density lipoprotein cholesterol in coronary atherosclerosis group were significantly higher than those in coronary normal group:18.6%(127/681) vs. 14.2%(103/727), 64.6%(440/681) vs. 45.8%(333/727), 48.5%(330/681) vs. 22.7%(165/727), (58.9 ± 12.2) years vs. (56.7 ± 13.1) years, (25.6 ± 4.3) kg/m2 vs. (24.9 ± 4.5) kg/m2, (70.28 ± 15.94)μmol/L vs. (52.79 ± 12.75)μmol/L, (6.82 ± 2.73) mmol/L vs. (5.57 ± 2.35) mmol/L, (7.86 ± 4.38)μmol/L vs. (5.63 ± 3.71)μmol/L and (3.32 ± 0.69) mmol/L vs. (2.28 ± 0.57) mmol/L, and there were statistical differences (P24 kg/m2) and total bile acid levels were risk factors of coronary atherosclerosis (P<0.05 or<0.01). Conclusions The serum total bile acid level is positively correlated with the severity of coronary atherosclerosis, which may be one of the independent risk factors for coronary atherosclerosis.