Liver is the primary site of alcohol metabolism and is the primary organ that is injured by alcohol. Though it has long been clear that ethanol is metabolized to acetate in hepatocytes, it is known that the acetate isn't burned as fuel in the liver or directly converted to fat in the liver. The knowledge that the calories from ethanol are burned in the muscle may have inhibited people from considering whether any further metabolism of acetate occurs in the liver and whether this could be linked to alcohol hepatopathology. Recently, liver mitochondrial protein acetylation has been described in response to alcohol ingestion. This means that liver mitochondrial proteins are tagged with the exact same molecule that liver produces when we drink alcohol. We also know from genetics that many mitochondrial proteins with the acetylation tag are inhibited by this adduct and that mice that have this modification accumulate in mitochondrial proteins get fatty liver. In this proposal, a straightforward mechanism from ethanol to acetylated liver mitochondrial proteins is proposed and will be tested. Moreover, nicotinamide riboside, a vitamin that has the property of increasing NAD+ in mitochondria, is proposed as an agent to protect against the development of alcohol-derived mitochondrial protein hyperacetylation and alcoholic fatty liver.
Alcoholic liver disease is a major health problem for which millions of Americans are at risk. Research is proposed to determine the connection between the production of acetate and the linkage of acetate to proteins required for the metabolism of fat. A newly discovered vitamin will also be tested for reversing this destructive process. If the mechanism is demonstrated in mice, this research could benefit humans within 2-3 years.
| Fletcher, Rachel S; Ratajczak, Joanna; Doig, Craig L et al. (2017) Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Mol Metab 6:819-832 |
| Ratajczak, Joanna; Joffraud, Magali; Trammell, Samuel A J et al. (2016) NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun 7:13103 |
| Trammell, Samuel A J; Weidemann, Benjamin J; Chadda, Ankita et al. (2016) Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep 6:26933 |
| Trammell, Samuel A J; Schmidt, Mark S; Weidemann, Benjamin J et al. (2016) Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 7:12948 |
| Trammell, Samuel A J; Brenner, Charles (2015) NNMT: A Bad Actor in Fat Makes Good in Liver. Cell Metab 22:200-1 |
