Uridine, Orotate, and Mitochondrial Damage in Liver Disease

One model of fatty liver disease, in which damage to mitochondria in hepatocytes plays a big role (a representative article: http://www.ncbi.nlm.nih.gov/pubmed/15489566), is to administer orotate (the conjugate base of orotic acid) to animals. It's not clear why it's so toxic, and it isn't clear what the main mechanisms are. It's mind-bending, but I think it's become pretty clear, in all the vast "orotate-induced fatty liver" literature, that understanding orotate metabolism and the de novo pyrimidine biosynthetic pathway is likely to be important for understanding liver disease. Fatty liver disease is very common, and I forget what the percentage of the population is that "has" it. It usually has to be diagnosed with transabdominal ultrasound and can't reliably be diagnosed with blood tests of liver enzymes.

Orotate is an intermediate in the de novo formation of uridine, from which all other pyrimidines are made. I saw one article showing that orotate directly inhibits phosphatidylcholine formation at both steps, but I can't find it now. It's interesting that exogenous uridine inhibits orotate formation by inhibiting carbamoyl-phosphate synthetase activity (via UDP, UTP, UDP-glucose and other UDP-sugars) and, via UMP, orotate monophosphate decarboxylase (http://www.ncbi.nlm.nih.gov/pubmed/9357323). I'm thinking that may be one way exogenous uridine can work in treating fatty liver disease due to some drugs (http://www.ncbi.nlm.nih.gov/pubmed/17187420). It's mainly been used in people taking antiretrovirals for HIV and experience lactic acidosis due to liver damage or broader toxicity. It's hard to organize these references, but I know there are lots of human studies. Here's another one in animals: (http://www.ncbi.nlm.nih.gov/pubmed/18163507). The nucleoside analogue fialuridine was used in a trial to treat hepatitis B infections and caused liver failure in a striking manner, and I think it was never researched after that. The authors of this article think that fialuridine was incorporated into mtDNA and caused mitochondrial toxicity (http://content.nejm.org/cgi/content/full/333/17/1099), and exogenous uridine didn't help anyone in that trial (probably partly because the damage was too great). This type of thing is interesting with regard to mitochondrial functioning, because the same concepts can apply to disease states outside the liver. Another big mechanism whose dysregulation can play a big role in liver disease is the regulation of the directionality of S-adenosylhomocysteine hydrolase and the activities of SAM-e-dependent methyltransferases (http://www.fasebj.org/cgi/content/full/16/1/15). The relationship of orotate to nucleotide metabolism is interesting, and I'm trying to learn about the relationships of that to folic acid metabolism.