The role of CGI-58/ABHD5 in lipid metabolism, inflammation, and insulin action.

摘要

Cells normally store lipids as a source of energy, molecular building blocks, and signaling molecules. Under conditions of excess caloric storage such as obesity, lipids can accumulate to harmful levels and lead to inflammation and metabolic diseases like fatty liver and diabetes. In 2001, a novel protein known as Comparative Gene Identification 58 (CGI-58) was discovered to regulate cellular levels of triglyceride, a major lipid storage molecule. Humans with genetic mutations in CGI-58 accumulate triglyceride throughout their bodies and have a skin defect, fatty liver disease, and neurological disabilities. Research done at the biochemical level has found that CGI-58 serves as an activator of an enzyme known as Adipose Triglyceride Lipase (ATGL), which breaks down triglyceride. However, human ATGL mutations do not have the same effect as CGI-58 mutations, suggesting that CGI-58 has an unknown function. The purpose of this dissertation research is to advance the understanding of CGI-58 at a physiological level. In this work, we show that mice lacking CGI-58 developed severe fatty liver disease but paradoxically did not develop liver inflammation and diabetes. It is known that inflammation can interfere with insulin signaling and lead to Type 2 diabetes, in which a defective response to insulin causes high blood sugar. The absence of CGI-58 decreased the activation of inflammatory proteins and increased the response to insulin in the liver. We discovered that CGI-58 is necessary for the generation of certain lipids that can act as signaling mediators of inflammation. Next, we tested whether CGI-58 is an activator of ATGL-mediated triglyceride breakdown at the physiological level and whether this function fully explains the triglyceride accumulation caused by CGI-58 mutations. Absence of CGI-58 indeed decreased the enzymatic activity of ATGL in the liver and fat tissue, but we found that CGI-58 also controlled liver triglyceride levels through a separate function. This dissertation significantly advances the understanding of the disease caused by CGI-58 mutations in humans. Building upon the foundation of this work, future studies of these newly discovered functions of CGI-58 could lead to improved understanding and treatment of non-alcoholic fatty liver disease, inflammation, and Type 2 diabetes.