Role of Comparative Gene Identification-58 in Nonalcoholic Fatty Liver Disease
With non-alcoholic fatty liver disease (NAFLD) now being the most common liver illness and non-alcoholic steatohepatitis (NASH) on the rise to be the main indication for liver transplantation (1), the global disease burden is tremendous. Moreover, NAFLD-associated hepatocellular carcinoma (HCC) with or without cirrhotic development is another disease with potentially lethal consequence. NAFLD shows slow progression, transformation to NASH only affects around 5-10% of all patients (2) and development of decompensated cirrhosis or HCC is even less common. However, due to the high prevalence of this disease group, even very low transformation rates translate to a great number of patients. Modern hepatology integrates biomolecular research and microscopic cell injury models to explain the multi-faceted etiology of metabolic and cholestatic liver disease in what is known as the ‘multiple hit theory’. The first ‘hit’ being lipid accumulation commonly associated with obesity and other metabolic diseases, the liver is overwhelmed with lipid storing, partitioning and compensating the increased workload. Both direct lipotoxicity as well as decompensation and activation of proapoptotic pathways lead to the following ‘hits’ including endoplasmic reticulum (ER) stress, mitochondrial dysfunction, inflammation, further induction of apoptosis and fibrosis.
Lipases play a prominent role in these cellular processes as they activate lipolysis and provide non-esterified fatty acids (NEFA) within various tissues for further use. The first and ratelimiting step in lipid hydrolysis is conversion of triacylglycerol to diacylglycerol via Patatin-like phospholipase domain-containing protein 2/adipose triglyceride lipase (PNPLA2/ATGL). It has been shown that comparative gene identification-58 (CGI-58) is an important stimulator of ATGL in lipolysis. However, early data on CGI-58 liver-specific knockout (LKO) mice shows more severe steatosis than ATGL-LKO (3), implicating an ATGL-independent role of CGI-58 in lipolysis. A very recent study (4) has shown potential interactions between CGI-58 and another member of the PNPLA family, namely PNPLA3. They propose the possibility that PNPLA3 sequesters CGI-58 such that its lipolytic activity is impaired. Aim of this study is to evaluate various hypotheses on the CGI-58-associated mechanisms involved in lipid metabolism and NAFLD as shown in figure 1.
- What are the characteristics of CGI-58 in chow vs. methionine-choline deficient (MCD) diet in lipid hydrolysis and how is the lipid metabolism affected by inhibiting lysophosphatidic acid acyl transferase (LPAAT) activity of CGI-58 upon liver-specific knockout in mice?
- In human and murine cell culture, what is the in vitro mechanism of action by which CGI-58 modulates lipid hydrolysis in the presence of and in absence of ATGL? How is the interaction between CGI-58 and PNPLA3?
- Are CGI-58-LKO mice more susceptible to liver injury? How does CGI-58 interact with hepatic stellate cells in mice and humans? What is the effect of CGI-58-LKO on infiltrated and residential macrophages?
- Does CGI-58-LKO in a long-term observation induce HCC and can thus serve as a metabolic HCC model?
Methods and Skills:
Western Blot, PCR, immunohistochemistry, cell culture