The lamprey has evolved effective adaptive strategies to compensate for the lack of a biliary apparatus in the adult by up-regulation of organic anion and bile acid transporter orthologs in the kidney and by altering bile acid composition.1 The authors in the current study found that petromyzonol sulfate, the major bile salts in lamprey larva, is cytotoxic, but is converted to phosphatase inhibitor library the markedly less toxic 3-keto-petromyzonol sulfate in the adult. Humans with
obstructive cholestasis mirror some of these adaptations by up-regulation of exporters such as MRP4, MRP3, and OSTα/OSTβ on the liver basolateral membrane and by down-regulating bile acid biosynthesis. There is also up-regulation of pathways for bile acid detoxification through hydroxylation (phase I) and conjugation (phase II) via sulfation and glucuronidation, and at least in animal models up-regulating renal organic anion transporters.18 These strategies are beneficial and probably attenuate liver injury, but in most cases of biliary BAY 57-1293 manufacturer atresia are not effective in preventing progressive liver disease. It is possible that agonists could be developed that specifically target adaptive pathways for biotransformation and transport, possibly acting through nuclear receptors such as FXR, VDR, CAR, and PXR. ”
“Chronic inflammation is strongly associated with an increased risk for hepatocellular carcinoma (HCC) development. The multidrug resistance 2 (Mdr2)–knockout
(KO) mouse (adenosine triphosphate–binding cassette b4−/−), a model of inflammation-mediated HCC, develops chronic cholestatic hepatitis at an early age and HCC at an adult age. To delineate factors contributing to hepatocarcinogenesis, we compared the severity of early chronic hepatitis and late HCC development in two Mdr2-KO strains: Friend virus B-type/N (FVB) and C57 black 6 (B6). We demonstrated
that hepatocarcinogenesis was significantly less efficient in the Mdr2-KO/B6 mice versus the Mdr2-KO/FVB mice; this difference was more prominent in males. Chronic hepatitis in the Mdr2-KO/B6 males was more severe at 1 month of age but was less severe at 3 months of age in comparison with MCE公司 age-matched Mdr2-KO/FVB males. A comparative genome-scale gene expression analysis of male livers of both strains at 3 months of age revealed both common and strain-specific aberrantly expressed genes, including genes associated with the regulation of inflammation, the response to oxidative stress, and lipid metabolism. One of these regulators, galectin-1 (Gal-1), possesses both anti-inflammatory and protumorigenic activities. To study its regulatory role in the liver, we transferred the Gal-1–KO mutation (lectin galactoside-binding soluble 1−/−) from the B6 strain to the FVB strain, and we demonstrated that endogenous Gal-1 protected the liver against concanavalin A–induced hepatitis with the B6 genetic background but not the FVB genetic background.