TNFalpha-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish S-adenosylhomocysteine hydrolase.
Hepatic steatosis and liver degeneration are prominent features of the zebrafish ducttrip (dtp) mutant phenotype. Positional cloning identified a causative mutation in the gene encoding S-adenosylhomocysteine hydrolase (Ahcy). Reduced Ahcy activity in dtp mutants led to elevated levels of S-adenosylhomocysteine (SAH) and, to a lesser degree, of its metabolic precursor S-adenosylmethionine (SAM). Elevated SAH in dtp larvae was associated with mitochondrial defects and increased expression of tnfa and pparg, an ortholog of the mammalian lipogenic gene. Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae, whereas the overexpression of tnfa and the hepatic phenotype were unchanged in dtp larvae reared under germ-free conditions. These data identify an essential role for tnfa in the mutant phenotype and suggest a direct link between SAH-induced methylation defects and TNF expression in human liver disorders associated with elevated TNFalpha. Although heterozygous dtp larvae had no discernible phenotype, hepatic steatosis was present in heterozygous adult dtp fish and in wild-type adult fish treated with an Ahcy inhibitor. These data argue that AHCY polymorphisms and AHCY inhibitors, which have shown promise in treating autoimmunity and other disorders, may be a risk factor for steatosis, particularly in patients with diabetes, obesity and liver disorders such as hepatitis C infection. Supporting this idea, hepatic injury and steatosis have been noted in patients with recently discovered AHCY mutations.
Matthews
Randolph P
RP
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Lorent
Kristin
K
Mañoral-Mobias
Rafael
R
Huang
Yuehua
Y
Gong
Weilong
W
Murray
Ian V J
IV
Blair
Ian A
IA
Pack
Michael
M
D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007814:Larva / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008715:Methionine; D008930:Mitochondria, Liver / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D018384:Oxidative Stress; D010641:Phenotype; D013045:Species Specificity; D014372:Tubercidin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
D017931:DNA Primers; D014409:Tumor Necrosis Factor-alpha; D029961:Zebrafish Proteins; C018258:3-deazaadenosine; D008715:Methionine; D043383:Adenosylhomocysteinase; D014372:Tubercidin