cholecalciferol and Cholestasis

Liver cholestasis is a complex disease of broad etiologies. Hedgehog (Hh) signaling has been shown to play a pivotal role in modulating liver repair post cholestatic liver injury. We here investigated the role of vitamin D in experimental liver cholestasis induced by bile-duct ligation (BDL) in rats. Male Sprague Dawley rats underwent BDL surgery and two weeks post-surgery; vitamin D was administered daily for two weeks. Serum markers of hepatocellular integrity were measured and fibrosis was detected by measuring α-SMA and hepatic TGF-β1 as well as hepatic collagen content. Hh signaling was evaluated by measuring Smo and Gli1 levels. Histopathological examination of hepatic tissue was performed. Vitamin D alleviated obstructive cholestatic damage as illustrated by total bilirubin as well as gamma glutamyl transferase (γ-GT) serum levels. It also alleviated hepatocellular damage as suggested by reducing elevated serum aminotransferases induced by BDL. Antifibrotic activity of vitamin D was confirmed by decrease in mRNA and protein expression of α-SMA, as well as collagen content in hepatic tissue. Furthermore, vitamin D suppressed BDL-induced elevated hepatic TGF-β1 mRNA and protein levels. BDL activated Hh signaling and upregulated its upstream component smoothened (Smo) and downstream target gene Gli1. Treatment with vitamin D reduced Smo mRNA levels and suppressed hepatic Gli1 mRNA and protein levels. Molecular docking of vitamin D to Smo revealed that vitamin D binds similarly to its endogenous cholesterol ligand and blocks its activation. These results demonstrate that vitamin D mitigated cholestatic liver injury through inhibiting Hh signaling.

Topics: Animals; Bile Ducts; Cholecalciferol; Cholestasis; Extracellular Matrix Proteins; Hedgehog Proteins; Ligation; Liver; Liver Cirrhosis; Male; Molecular Docking Simulation; Rats, Sprague-Dawley; Signal Transduction; Smoothened Receptor; Transforming Growth Factor beta; Vitamins; Zinc Finger Protein GLI1

To study the effects of acute and chronic cholestasis on vitamin D metabolism we investigated six cases of acute extrahepatic obstructive jaundice and eight cases of primary biliary cirrhosis (PBC) (three supplemented with vitamin D). Plasma 25-hydroxyvitamin D (25OHD) was low in the patients with PBC unsupplemented with vitamin D but normal in obstructive jaundice. None of the patients with PBC showed radiological or histological evidence of osteomalacia. In PBC, dietary intake of vitamin D was low but response to ultra-violet irradiation of the skin was normal even in those with a considerably raised serum bilirubin. Patients with PBC or obstructive jaundice had low levels of 25 hydroxyvitamin D binding protein which correlated with the serum albumin. The half-life of intravenously injected (3)H vitamin D(3) ((3)HD(3)) and the subsequent production of (3)H 25OHD were normal in all the patients with obstructive jaundice and in most with PBC. The two patients with PBC who produced less (3)H 25OHD than expected were receiving vitamin D supplements. The urinary tritium ((3)H) excretion after the injection of (3)HD(3) correlated with the serum bilirubin. After the injection of (3)H 25OHD(3) the urinary excretion of (3)H was minimal and did not correlate with the serum bilirubin, suggesting that the radioactivity appearing in the urine after the (3)H vitamin D(3) injection was associated with vitamin D metabolites other than 25OHD. Factors contributing to the low plasma 25OHD in primary biliary cirrhosis may be a low dietary intake of vitamin D, inadequate exposure to ultra-violet light, and a tendency to urinary wastage of vitamin D metabolites.

Topics: Acute Disease; Adult; Aged; Cholecalciferol; Cholestasis; Cholestasis, Extrahepatic; Chronic Disease; Ergocalciferols; Female; Half-Life; Humans; Hydroxycholecalciferols; Liver Cirrhosis, Biliary; Male; Middle Aged; Ultraviolet Therapy; Vitamin D

Topics: Adult; Aged; Biological Transport; Cholecalciferol; Cholestasis; Chromatography, Gel; Chromatography, Thin Layer; Chylomicrons; Female; Humans; Intestinal Absorption; Lymph; Male; Middle Aged; Thoracic Duct; Triglycerides; Tritium; Vitamin E; Vitamin K 1

Topics: Acetates; Aged; Alkenes; Amines; Biological Transport; Carbon Isotopes; Cholecalciferol; Cholestasis; Diet; Fatty Acids; Female; Humans; Intestinal Absorption; Lymph; Middle Aged; Thoracic Duct; Tritium; Vitamin E; Vitamin E Deficiency; Vitamin K 1

Topics: Adult; Aged; Celiac Disease; Cholecalciferol; Cholestasis; Chromatography, Thin Layer; Feces; Humans; Intestinal Absorption; Malabsorption Syndromes; Middle Aged; Urine