deoxycholic-acid and Fatty-Liver

Our previous study indicated that hepatic bile acids (BAs) may have deposited and stimulated the pathogenesis of a high fat-cholesterol (HFC) diet-induced fibrotic steatohepatitis in stroke-prone spontaneously hypertensive 5/Dmcr rats, based on dysregulated BA homeostasis pathways. We aimed to further characterize BA profiles in liver and evaluate their relationships to liver injury using this model.. Hepatic 21 BA levels were determined by ultra-performance liquid chromatography-tandem mass spectrometry, and their correlations with macrovesicular steatosis score, serum alanine aminotransferase (ALT) level and quantified fibrotic area were assessed using Spearman and Pearson correlations.. Compared to control, BAs highly accumulated in HFC-fed rat liver at 2 weeks: cholic acid (CA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) were major species, thereafter, levels of CA and DCA declined, but CDCA species persistently increased, which induced a decrease in total CA/total CDCA ratio at 8 and 14 weeks. CDCA species positively, while total CA/total CDCA negatively, correlated with macrovesicular steatosis score, serum ALT and quantified fibrotic area. Unlike control, total ursodeoxycholic acid was minor in HFC-fed rat liver, and inversely correlated to aforementioned indicators of liver injury; total glyco-BAs, rather than tauro-BAs, were predominant in HFC-fed rat liver, and positively correlated with macrovesicular steatosis score. Moreover, its ratio to total tauro-BAs positively correlated with each parameter of liver injury, while inverse associations were detected for total tauro-BAs.. Hepatic BA accumulation may potentiate liver disease. CDCA and glyco-BAs play a more important role in the pathogenesis of fibrotic steatohepatitis.

Topics: Animals; Biomarkers; Chenodeoxycholic Acid; Cholic Acid; Chromatography, Liquid; Deoxycholic Acid; Diet, High-Fat; Fatty Liver; Liver; Liver Cirrhosis; Male; Non-alcoholic Fatty Liver Disease; Random Allocation; Rats; Tandem Mass Spectrometry

Topics: Animals; Deoxycholic Acid; Fatty Liver; Humans; Intestines; Liver Neoplasms; Mice; Microbiota

Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bile Acids and Salts; Carcinoma, Hepatocellular; Cells, Cultured; Cellular Senescence; Cytokines; Deoxycholic Acid; Dietary Fats; Disease Models, Animal; DNA Damage; Fatty Liver; Gastrointestinal Tract; Hepatic Stellate Cells; Humans; Interleukin-1beta; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Phenotype; Risk Factors

The proinflammatory effect of high-fat diet has been observed beyond the cardiovascular system, but there is little evidence to support its role in triggering inflammatory bowel disease. GPx1/2-double-knockout (DKO) mice deficient in 2 intracellular glutathione peroxidases, GPx1 and GPx2, on a C57BL/6 (B6) background, have mild ileocolitis on a conventional chow.. We fed B6 DKO mice 2 atherogenic diets to test the dietary effect on atherosclerosis and ileocolitis. Both atherogenic diets have high cholesterol-the Chol+/CA diet has cholic acid (CA), and the Chol+ diet has no CA.. The Chol+/CA diet induced severe colitis, but not ileitis, in the DKO mice compared with the Chol+ and the Chol- control diet. On the Chol+/CA diet, the wild-type (WT) mice had levels of aortic lesions and hypercholesterolemia similar to those of DKO mice but had no intestinal pathology. The diet-associated inflammatory responses in the DKO mice included increased colonic proinflammatory serum amyloid A3 expression, plasma lipopolysaccharide, and TNF-α levels. The Chol+/CA diet lowered the expression of the unfolded protein response genes ATF6, CHOP, unspliced Xbp(U) , and Grp78/Bip, in WT and DKO mice compared with mice on the Chol- diet.. We concluded that a cholesterol diet weakens the colon unfolded protein response, which can aggravate spontaneous colitis, leading to gut barrier breakdown. GPx has no impact on atherosclerosis without ultrahypercholesterolemia.

Topics: Animals; Atherosclerosis; Blotting, Western; Cholesterol; Colitis; Crohn Disease; Deoxycholic Acid; Diet, Atherogenic; Endoplasmic Reticulum Chaperone BiP; Fatty Liver; Feces; Female; Gas Chromatography-Mass Spectrometry; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Inflammation; Inflammation Mediators; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Rate; Tumor Necrosis Factor-alpha

The pathogenesis of steatohepatitis remains largely unknown; however, bile acids may play a role as potential mediators of liver damage. The aim of this study was to characterize bile acid profiles in liver tissue of patients with steatohepatitis.. Bile acid composition was determined by gas-liquid chromatography in liver tissue from patients with nonalcoholic steatohepatitis (NASH; n=15), patients with alcoholic steatohepatitis (ASH; n=14), and controls (n=8). Liver biopsies were graded for steatosis, inflammation, and fibrosis.. Bile acids were moderately increased in liver tissue of steatohepatitis patients compared with controls (P<0.05). Deoxycholic, chenodeoxycholic, and cholic acids were elevated by 92, 64, and 43%, respectively, in patients with steatohepatitis (P<0.05). Cholic acid was the prevailing bile acid in NASH patients and in controls. More hydrophobic bile acid species were elevated in ASH patients compared with controls (P<0.05). Significant correlations were found in NASH patients between hepatic chenodeoxycholic acid and fibrosis, and between cholic acid and trihydroxy/dihydroxy bile acids and inflammation (P<0.05). In patients with ASH, cholic acid and trihydroxy/dihydroxy bile acids were correlated with steatosis (P<0.01).. This study shows a distinct pattern of bile acids in the liver of patients with steatohepatitis. Further, the association between bile acids and histological liver injury suggests an association of specific bile acids and disease progression, possibly through bile acid-induced liver injury.

Topics: Adult; Bile Acids and Salts; Biopsy; Chenodeoxycholic Acid; Cholic Acid; Chromatography, Gas; Deoxycholic Acid; Disease Progression; Fatty Liver; Fatty Liver, Alcoholic; Female; Humans; Liver; Male; Middle Aged; Severity of Illness Index

Urinary bile acid excretion and liver morphology were compared in 25 patients with cystic fibrosis (CF). None showed clinical signs of liver disease. Most of the patients had normal liver function tests. Bile acids were determined in 24-h samples by a modification of the method of Almé. All patients had increased urinary excretion of trihydroxy bile acids, mainly cholic, 3 beta, 7 beta, 12 alpha- and 3 alpha, 7 beta, 12 alpha-trihydroxy-5 beta-cholanoic acids. Lithocholic acid excretion was lower in CF than in normal children. The urinary excretion of 3 beta-hydroxy-5-cholenoic acid was not increased in CF. In three patients with cirrhosis the urinary excretion of chenodeoxycholic acid was increased. The ratio of cholic to 3 beta-hydroxy-5-cholenoic acids was increased in all but three patients, and the ratio of chenodeoxycholic to 3 beta-hydroxy-5-cholenoic acids was increased in those with cirrhosis. These ratios differed more between cirrhotic and non-cirrhotic CF patients in this series than the ratio of cholic to chenodeoxycholic acids.

Topics: Adolescent; Adult; Bile Acids and Salts; Child; Child, Preschool; Cholic Acids; Cystic Fibrosis; Deoxycholic Acid; Fatty Liver; Humans; Infant; Lithocholic Acid; Liver; Liver Cirrhosis; Liver Function Tests; Taurolithocholic Acid

Topics: Adult; Bile; Bile Acids and Salts; Bilirubin; Chenodeoxycholic Acid; Cholic Acids; Deoxycholic Acid; Fatty Liver; Female; Glycine; Humans; Ileum; Jejunum; Lithocholic Acid; Liver; Liver Cirrhosis; Liver Diseases; Male; Obesity; Postoperative Complications; Protein Deficiency; Sulfuric Acids; Taurine