SIRT3 is an enzyme vital to maintaining a balance between fat buildup and breakdown in the liver. Mice lacking the gene coding for SIRT3 show enhanced fatty liver disease when fed a high-fat diet, but it’s unknown how or whether SIRT3 can actively prevent fatty liver disease in such mice. A recent study examined the molecular effects of a standard diet and a high-fat diet in wild-type mice and in mice missing the gene coding for SIRT3. Feeding SIRT3-less mice a high-fat diet aggravated fatty liver disease and reduced the protective, fat-oxidizing effect of the molecule PPARα. Similarly, levels of LIPIN1, a protective protein that covers for the loss of SIRT3, were reduced when mice were fed a high-fat diet. In the absence of SIRT3, exposure to a fatty diet promoted the production of proteins that absorb fats through the regulatory molecule NRF2. While it remains to be seen how or whether these same mechanisms operate in humans, the findings could lead to a better understanding of how fatty liver disease progresses and how it might be stopped.