Proteolytic shedding of CD46 from human hepatocytes indicates liver stress.

Background: Routine liver function tests capture information about the metabolic and inflammatory condition of the liver, but we lack sensitive biomarkers of early hepatocyte stress. In humans, soluble CD46 (sCD46) levels in blood were recently identified as an accurate biomarker of hepatic steatosis. Here, we explore the diagnostic utility of sCD46 in other liver diseases. Methods: We developed, optimised and validated an ELISA that facilitates measurements of human sCD46 in plasma, serum and culture supernatants. Then, we analysed mechanisms that lead to the release of sCD46 and identified its role in various hepatic stress conditions. Results: We discovered that prostaglandin E2 (PGE2) drives upregulation of matrix metalloproteinase (MMP)-1 in fat-loaded hepatocytes, leading to proteolytic shedding of CD46. We further found that sCD46 release was increased by viral, toxic and hypoxic stresses. Conclusions: sCD46 appears to be a promising biomarker with potential applications in the detection of early liver diseases or monitoring therapeutic responses, which could complement established diagnostic algorithms because sCD46 release is uniquely responsive to hepatocyte stress.