Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis.
Journal of Hepatology 64(3):674 (2016)
Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate back to the liver for further biliary secretion. Therefore, pharmacological inhibition of the ileal apical sodium-dependent BA transporter (ASBT/SLC10A2) may protect against BA-mediated cholestatic l...
Epiplakin attenuates experimental mouse liver injury by chaperoning keratin reorganization.
Journal of Hepatology 62(6):1357 (2015)
Epiplakin is a member of the plakin protein family and exclusively expressed in epithelial tissues where it binds to keratins. Epiplakin-deficient (Eppk1(-/-)) mice displayed no obvious spontaneous phenotype, but their keratinocytes showed a faster keratin network breakdown in response to stress...
Resolution of liver fibrosis requires myeloid cell-driven sinusoidal angiogenesis.
Hepatology 61(6):2042 (2015)
Angiogenesis is a key feature of liver fibrosis. Although sinusoidal remodeling is believed to contribute to fibrogenesis, the impact of sinusoidal angiogenesis on the resolution of liver fibrosis remains undefined. Myeloid cells, particularly macrophages, constantly infiltrate the fibrotic live...
24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis.
Journal of Hepatology 62(4):871 (2015)
Intrahepatic granuloma formation and fibrosis characterize the pathological features of Schistosoma mansoni infection. Based on previously observed substantial anti-fibrotic effects of 24-nor-ursodeoxycholic acid (norUDCA) in Abcb4/Mdr2(-/-) mice with cholestatic liver injury and biliary fibrosi...
Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth.
Nature 491(7423):254 (2012)
Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tum...
Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice.
Gastroenterology 143(3):765 (2012)
Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice.
Using cholestatic and hepatotoxic models of liver injury, we compared the development of liver fibrosis in wild-type mice with that ...
Animal models of biliary tract injury.
Current Opinion in Gastroenterology 28(3):239 (2012)
Cholestatic liver diseases with bile duct injury and biliary fibrosis account for a significant percentage of patients with end-stage liver disease and undergoing liver transplantation. A number of different animal models have been established and have added substantially to our understanding of...
Xenobiotic-induced liver injury and fibrosis.
Expert Opinion on Drug Metabolism and Toxicology 8(5):571 (2012)
Many different drugs and xenobiotics (chemical compounds foreign to an organism) can injure the bile duct epithelium and cause inflammatory bile duct diseases (cholangiopathies) ranging from transient cholestasis to vanishing bile duct syndrome, sclerosing cholangitis with development of biliary...
The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice.
Hepatology 53(5):1730 (2011)
Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a multicomponent enzyme that mediates electron transfer from nicotinamide adenine dinucleotide phosphate to molecular oxygen, which leads to the production of superoxide. NOX2/gp91(phox) is a catalytic subunit of NOX expressed in phago...
Fibrosis in autoimmune and cholestatic liver disease.
Best Practice & Research Clinical Gastroenterology 25(2):245 (2011)
Autoimmune and cholestatic liver disease account for a significant part of end-stage liver disease and are leading indications for liver transplantation. Especially cholestatic liver diseases (primary biliary cirrhosis and primary sclerosing cholangitis) appear to be different from other chronic...
Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver.
PNAS 108(1):308 (2011)
Cirrhosis is the end result of chronic liver disease. Hepatic stellate cells (HSC) are believed to be the major source of collagen-producing myofibroblasts in cirrhotic livers. Portal fibroblasts, bone marrow-derived cells, and epithelial to mesenchymal transition (EMT) might also contribute to ...
Role and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in hepatic fibrosis.
Hepatology 52(4):1420 (2010)
Reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate oxidase (NOX) is required for liver fibrosis. This study investigates the role of NOX in ROS production and the differential contribution of NOX from bone marrow (BM)-derived and non-BM-derived liver cells. He...
Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice.
Gastroenterology 139(3):987 (2010)
Chronic injury changes the fate of certain cellular populations, inducing epithelial cells to generate fibroblasts by epithelial-to-mesenchymal transition (EMT) and mesenchymal cells to generate epithelial cells by mesenchymal-to-epithelial transition (MET). Although contribution of EMT/MET to e...
Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice.
Hepatology 51(3):1027 (2010)
The origin of fibrogenic cells in liver fibrosis remains controversial. We assessed the emerging concept that hepatocytes contribute to production of extracellular matrix (ECM) in liver fibrosis through epithelial-mesenchymal transition (EMT). We bred triple transgenic mice expressing ROSA26 sto...
Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.
Cell 140(2):197 (2010)
Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly ...
Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis.
PNAS 107(2):844 (2010)
TGF-beta-activated kinase 1 (TAK1) is a MAP3K family member that activates NF-kappaB and JNK via Toll-like receptors and the receptors for IL-1, TNF-alpha, and TGF-beta. Because the TAK1 downstream molecules NF-kappaB and JNK have opposite effects on cell death and carcinogenesis, the role of TA...
Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition.
Gastroenterology 138(1):347 (2010)
c-Jun N-terminal kinase (JNK) is activated by multiple profibrogenic mediators; JNK activation occurs during toxic, metabolic, and autoimmune liver injury. However, its role in hepatic fibrogenesis is unknown.
JNK phosphorylation was detected by immunoblot analysis and confocal immunofluorescent...
Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice.
Hepatology 50(3):929 (2009)
The renin-angiotensin system (RAS) plays a major role in liver fibrosis. Recently, a homolog of angiotensin-converting-enzyme 1 (ACE1), termed ACE2, has been identified that appears to be a negative regulator of the RAS by degrading Ang II to Ang(1-7). The aim of this study was to characterize t...
Microsomal triglyceride transfer protein polymorphism (-493G/T) is associated with hepatic steatosis in patients with chronic hepatitis C.
Liver International 29(4):557 (2009)
Hepatic steatosis may promote progression of chronic hepatitis C (CHC). Microsomal triglyceride transfer protein (MTP) is required for assembly and secretion of ApoB lipoprotein and is implicated in hepatitis C virus (HCV)-related steatosis. The MTP -493G/T polymorphism may promote liver fat acc...
Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis.
Gastroenterology 135(5):1729 (2008)
Although angiogenesis is closely associated with liver fibrosis, the angiogenic factors involved in liver fibrosis are not well characterized. Angiopoietin 1 is an angiogenic cytokine indispensable for vascular development and remodeling. It functions as an agonist for the receptor tyrosine kina...