Novel molecular determinants of insulin clearance

This project explores a novel molecular axis linking adipose tissue and liver that may drive non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and liver fibrosis. Previous work has shown that CEACAM1, a plasma membrane glycoprotein expressed in hepatocytes, promotes insulin clearance in the liver and thereby influences insulin action and fat metabolism; reduced hepatic CEACAM1 is associated with NAFLD and progression to NASH.

Research has also identified FSP27, a protein in adipocytes that regulates lipolysis and fat metabolism; reductions in FSP27 in adipose tissue lead to increased free fatty acid release to the liver, promoting hepatic steatosis when hepatic oxidative capacity is exceeded. The central hypothesis of the collaboration is that FSP27-driven changes in adipose tissue alter hepatic CEACAM1 levels and that this “cross-talk” between fat and liver is a molecular driver of hepatic inflammation and fibrosis. Building on prior NIH-funded comparisons of CEACAM1 and FSP27 levels across human populations, this new effort will now investigate the molecular mechanism of FSP27–CEACAM1 interaction and its role in fibrosis development.

The preliminary data indicate that reducing FSP27 in mice lowers CEACAM1 in the liver and leads to hepatic inflammation and fibrosis. The current grant will further define whether manipulating CEACAM1 in the liver can block injury in models where FSP27 is reduced in adipose tissue, testing the therapeutic potential of increasing hepatic CEACAM1 to prevent or reverse fibrosis. If increasing CEACAM1 in such mouse models prevents liver injury, it would support a strategy of directly inducing CEACAM1 as a drug target to treat or prevent fibrosis in NASH. In addition to inter-tissue communication, the team will examine cell-autonomous fibrosis originating in liver stellate cells, which store fat. They will reduce FSP27 in stellate cells to determine whether this reduction lowers CEACAM1 locally and triggers fibrosis independent of adipose tissue-derived signals. This approach addresses both systemic adipose-to-liver signaling and intrahepatic drivers of fibrosis, with the goal of identifying molecular points of intervention. The collaboration brings complementary expertise: Najjar’s focus on hepatic CEACAM1 and its consequences for insulin clearance and lipid handling, and Puri’s expertise in adipocyte biology and FSP27 function.

The project is funded by an NIH award of more than $2 million over four years, enabling mechanistic studies in mouse models and molecular analyses aimed at discovering novel therapeutic targets. The work directly addresses a pressing clinical need: there are currently no FDA-approved drugs that cure liver fibrosis, and fibrosis is the most common indication for liver transplantation in progressive NASH. The team also highlights relevance to “lean NASH,” a form of disease not linked to obesity, where standard insulin-sensitizing treatments may be ineffective. By elucidating how FSP27 and CEACAM1 interact to cause hepatic inflammation and fibrosis, the research team aims to identify actionable molecular targets for interventions that could prevent or potentially reverse fibrosis, opening new therapeutic avenues for NASH and related metabolic liver diseases.