retinol-palmitate and Fatty-Liver

Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by mutations in the G6PC gene, encoding the catalytic subunit of glucose-6-phosphatase. Early symptoms include severe fasting intolerance, failure to thrive and hepatomegaly, biochemically associated with nonketotic hypoglycemia, fasting hyperlactidemia, hyperuricemia and hyperlipidemia. Dietary management is the cornerstone of treatment aiming at maintaining euglycemia, prevention of secondary metabolic perturbations and long-term complications, including liver (hepatocellular adenomas and carcinomas), kidney and bone disease (hypovitaminosis D and osteoporosis). As impaired vitamin A homeostasis also associates with similar symptoms and is coordinated by the liver, we here analysed whether vitamin A metabolism is affected in GSD Ia patients and liver-specific G6pc-/- knock-out mice. Serum levels of retinol and retinol binding protein 4 (RBP4) were significantly increased in both GSD Ia patients and L-G6pc-/- mice. In contrast, hepatic retinol levels were significantly reduced in L-G6pc-/- mice, while hepatic retinyl palmitate (vitamin A storage form) and RBP4 levels were not altered. Transcript and protein analyses indicate an enhanced production of retinol and reduced conversion the retinoic acids (unchanged LRAT, Pnpla2/ATGL and Pnpla3 up, Cyp26a1 down) in L-G6pc-/- mice. Aberrant expression of genes involved in vitamin A metabolism was associated with reduced basal messenger RNA levels of markers of inflammation (Cd68, Tnfα, Nos2, Il-6) and fibrosis (Col1a1, Acta2, Tgfβ, Timp1) in livers of L-G6pc-/- mice. In conclusion, GSD Ia is associated with elevated serum retinol and RBP4 levels, which may contribute to disease symptoms, including osteoporosis and hepatic steatosis.

Topics: Adolescent; Adult; Animals; Diterpenes; Fatty Liver; Female; Glucose-6-Phosphatase; Glycogen Storage Disease Type I; Humans; Inflammation; Liver; Male; Mice; Mice, Knockout; Osteoporosis; Retinoic Acid 4-Hydroxylase; Retinol-Binding Proteins, Plasma; Retinyl Esters; Vitamin A

Liver retinoid levels and the retinyl esters were examined in liver biopsy specimens from 70 patients with alcoholic and nonalcoholic liver diseases. There was a wide variation in the liver retinoid levels. The liver retinoid level was statistically significantly lower in 15 patients with alcoholic liver disease and a depressed Normotest (NT) value of less than 65% compared with patients with alcoholic liver disease and a normal NT value of greater than 65% (P less than 0.01). The mean serum retinol level in patients with alcoholic cirrhosis was 0.68 +/- 0.38 mumol/l compared with 1.99 +/- 1.14 mumol/l in patients with alcoholic fatty liver (P less than 0.03). The relative amount of retinyl oleate was increased in the alcoholic fatty liver compared with the nonalcoholic fatty liver (P less than 0.001).

Topics: Adult; Aged; Diterpenes; Ethanol; Fatty Liver; Fatty Liver, Alcoholic; Female; Humans; Liver; Liver Diseases; Liver Diseases, Alcoholic; Male; Middle Aged; Retinoids; Retinol-Binding Proteins; Retinyl Esters; Vitamin A