U.S. Department of Health and Human Services

Cell Signaling Pathways Point to Top Notch Solution for Fatty Liver Disease

​Scientists have identi​fied a cell signaling pathway that may contribute to the development of fatty liver disease and may also point to therapeutic solutions. Obesity is associated with several metabolic diseases, including type 2 diabetes and nonalcoholic fatty liver disease, or “NAFLD,” which is marked by fat accumulation in the liver. Treatment options for NAFLD are particularly limited. One mystery surrounding these obesity-associated metabolic diseases has been how some insulin-responsive pathways in liver cells, such as fat production, continue to function when insulin is elevated—ultimately, contributing to fatty liver—while others, such as suppression of glucose production, become resistant to the action of insulin. Researchers explored cell signaling pathways that could be responsible for the overproduction of fat in the liver associated with insulin resistance. They narrowed their search to a signaling pathway initiated at a receptor protein spanning the cell surface known as “Notch,” which regulates some metabolic functions in the liver, but is also well-known for its role in early development. After feeding mice a high-fat diet, the team saw greater Notch activity in the liver, along with more fat deposition in the organ. However, when mice were genetically altered to lack a key factor in the liver needed for Notch signaling, their livers showed less fat accumulation than in the non-genetically altered mice. Similar results were observed when Notch signaling was again disabled, this time in mice with a defective Notch receptor protein. To gather more evidence for their theory, they also created a mouse model in which Notch signaling was active all the time. In this model, they observed fat accumulation in the liver even though the mice were given a more balanced (non-high-fat) diet. Using the expression of some genes that are typically affected by the Notch signaling pathway as a readout, the scientists determined that Notch signaling acts through a molecule within the cell called mTorc1 to increase fat production in the liver. If studies in humans show a similar role for Notch signaling, this could be an important therapeutic target to block in treating NAFLD associated with obesity. This inding is especially promising in light of the fact that agents to inhibit Notch signaling are already available and being tested in clinical trials against other diseases.

Pajvani UB, Quang L, Kangsamaksin T, Kitajewski J,
Ginsberg HN, and Accili D. Inhibition of Notch uncouples
Akt activation from hepatic lipid accumulation by decreasing
mTorc1 stability. Nat Med 19: 1054-1061, 2013.