The Pathophysiologic Roles of Aldehyde and Folic Acid in Fatty Liver: a Joint Study of Human and Mice Models (2nd and 3rd Years)

Alcoholic fatty liver disease (AFLD) is defined as the presence of steatosis with excessive alcohol consumption, while non-alcoholic fatty liver disease (NAFLD) is defined by the non-alcoholic nature in the presence of fatty liver. Up to 90% of alcoholics have AFLD and around 7300 million individuals worldwide have NAFLD. Both AFLD and NFLALD are serious health problems worldwide, they are so similar that only a detailed history of alcohol intake can distinguish one from the other. These two diseases have similar pathological spectra, ranging from simple steatosis to hepatitis, cirrhosis and hepatocellular carcinoma, however, there are still no targeted therapies available. Because subjects with NAFLD produce more endogenous ethanol and aldehyde than controls, NAFLD is regarded actually an endogenous AFLD. Aldehyde dehydrogenase 2 detoxifies toxic aldehydes and has a key role in protecting the liver from alcohol. It also signifies the toxicity of aldehyde in AFLD. Besides, liver is the primary organ responsible for storage and metabolism of folic acid, which plays an essential role in one-carbon transfer reactions involved in nucleic acid biosynthesis, methylation reactions, and sulfur-containing amino acid metabolism. Significant correlation between low levels of folic acid with the high liver fat content has been noted. Aldehyde dehydrogenase is involved in the aldehyde and folic acid pathways and suggests the close interaction between the aldehyde and folic acid metabolisms. However, the roles of aldehyde and folic acid had never been elucidated simultaneously in fatty liver. Recently, we had elucidated the metabolic alterations [Clin Microbiol Infect. 2019; Eur J Clin Invest. 2019; Exp Ther Med. 2019] and extrahepatic impacts of various metabolic liver diseases (particularly hepatitis C, an important etiology for NAFLD) [Therap Adv Gastroenterol. 2019; Sci Rep. 2019] and built up several lines of mouse models of fatty liver. The current 3-year proposal thus is raised to investigate the associated pathways of aldehyde and folic acid, with a focus on genetic, proteomic, metabolomic profiles, to dissect the basis of fatty liver. In parallel, the potential therapeutic target will be probed in the mice with fatty liver. Based on the 1st year-work of the current proposal, we had published an article entitled " Metabolic Signature of Hepatic Fibrosis: From Individual Pathways to Systems Biology." in Cells (2019). We summarized the individual metabolic pathways and data from genetic, proteomic and metabolomic profiles as metabolic signature for hepatic fibrosis in fatty liver. In particular, the impacts of aldehyde and folic acid on hepatic fibrosis and fatty liver were discussed. This article had been downloaded over 400 times in recent 1 month. Additionally, we had enrolled 420 patients with fatty liver and surveyed their aldehyde and folic acid-related single nucleotide polymorphisms after a tough process to establish the protocols of PCR. We also had compared the phenotypes and blood biochemistry data from the mice with and without fatty liver. Two more year grant support is extremely demanded to accomplish the main goals of the current proposal. The proposal holds promise to provide therapeutic interventions targeting crucial factors to treat fatty liver.

Project ID:PC10907-1127
External Project ID:MOST109-2314-B182-024