Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis.

The liver is one of the main organs responsible for processing everything that mammals eat and drink. Nutrients absorbed by the gut like sugars and lipids (fats) are processed by the liver and are stored or distributed to provide energy to other organs. Sometimes these metabolic processes become unbalanced. This can lead to lipids accumulating in the liver – a process known as steatosis, which is a feature of human non-alcoholic fatty liver disease. In organs like the liver, cells are instructed how to behave via signaling pathways. A protein outside the cell signals to specific proteins inside, which switch on a set of target genes. One such pathway is the Hedgehog pathway, which primarily regulates tissue regeneration and the development of embryos. A component of this pathway is the Smoothened gene, which indirectly switches on proteins called GLI factors that regulate metabolic genes, including those involved in lipid metabolism. The Hedgehog pathway has been found to control the metabolism of lipids in fat tissue but it is not known whether it is important for lipid metabolism in the liver. Matz-Soja et al. investigated this possible role of the Hedgehog pathway in the liver using mice with a Smoothened gene that could be deleted specifically in that organ. This deletion disrupted Hedgehog signaling and led to lipids accumulating in the liver and eventually to steatosis. These changes were associated with an increase in the amounts and activityof several enzymes (and the proteins that regulate these enzymes) that help to synthesize lipids. Steatosis was also associated with low amounts of two of the three GLI factors; indeed, this seems to be key for triggering problems with lipid metabolism. Human livers with steatosis showed the same changes in levels of the GLI factors. Increasing the amount of GLI factors in liver cells taken from mice with steatosis reduced the accumulation of lipids and brought lipid metabolism back to its normal balance. A focus of future studies will be to understand how the Hedgehog signaling pathway interacts with other signaling pathways known to regulate liver lipid metabolism, such as insulin signaling. This knowledge will help clinicians to design new treatments for lipid-associated diseases like non-alcoholic fatty liver disease.