Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation

Abstract

SUMMARY Adipose Triglyceride Lipase (ATGL) and Comparative Gene Identification 58 (CGI-58) are critical regulators of triacylglycerol (TAG) turnover. CGI-58 is thought to regulate TAG mobilization by stimulating the enzymatic activity of ATGL. However, it is not known whether this coactivation function of CGI-58 occurs in vivo. Moreover, the phenotype of human CGI-58 mutations suggests ATGL-independent functions. Through direct comparison of mice with single or double deficiency of CGI-58 and ATGL, we show here that CGI-58 knockdown causes hepatic steatosis in both the presence and absence of ATGL. CGI-58 also regulates hepatic diacylglycerol (DAG) and inflammation in an ATGL-independent manner. Interestingly, ATGL deficiency, but not CGI-58 deficiency, results in suppression of the hepatic and adipose de novo lipogenic program. Collectively, these findings show that CGI-58 regulates hepatic neutral lipid storage and inflammation in the genetic absence of ATGL, demonstrating that mechanisms driving TAG lipolysis in hepatocytes differ significantly from those in adipocytes.

Critical roles for α/β hydrolase domain 5 (ABHD5)/comparative gene identification-58 (CGI-58) at the lipid droplet interface and beyond

“…A recent study demonstrated that HCV-core induced hepatic steatosis requires ATGL activity, yet unexpectedly is associated with increased interaction of ATGL and CGI-58 at the lipid droplet surface [46]. This results strongly suggests that CGI-58 and ATGL can interact at the hepatocyte lipid droplet surface, similar to what is know in adipocytes [19–25], yet unlike in adipocytes, this interaction is not coupled to ATGL activation and TAG hydrolysis [45,46]. Therefore, additional work is required to determine the functional consequence of ATGL-CGI-58 interaction in hepatocytes.…”

“…However, it is important to note that global ATGL−/− mice die prematurely due to cardiomyopathy, which makes it difficult to know whether long-term ATGL deficiency would indeed advance towards frank fibrosis. A recent study directly tested whether CGI-58 regulates TAG metabolism via an ATGL-dependent mechanism by knocking down CGI-58 in the liver of wild type or ATGL −/− mice [45]. This work demonstrated that CGI-58 can regulate hepatic steatosis and inflammation in the complete genetic absence of ATGL, indicating that CGI-58 regulates hepatic TAG metabolism and inflammation via ATGL-independent mechanisms [46].…”

“…1 & 2). However, CGI-58 can regulate TAG hydrolysis and cellular signaling in many other cell types including hepatocytes [45], keratinocytes [33], and several cancer cell lines [94] via an ATGL-independent mechanism. Given these ATGL-dependent and ATGL-independent roles for CGI-58, human mutations of either CGI-58 or ATGL are associated with some shared yet several divergent phenotypes [11].…”

“…CGI-58 knockdown in mice leads to increased hepatic DAG levels [41,42,45], and prevents the inflammatory cytokine-driven generation of several signaling lipids that can be derived from DAG [79]. Two recent reports also support the possibility that CGI-58 could play a direct role in the regulation of DAG metabolism or subcellular localization [42,110].…”

“…Second, CGI-58 co-activation broadens the selectivity of ATGL for the sn -2 position of TAG to include the sn -1 position, resulting in the generation of both sn -1,3 and sn -2,3 DAG [110]. It is important to note that ATGL deficiency decreases hepatic DAG levels, whereas CGI-58 knockdown increases hepatic DAG both in the presence or absence of ATGL [45]. Although the mechanism by which CGI-58 knockdown causes DAG accumulation within the lipid droplet/endoplasmic reticulum compartment is unknown, the reciprocal reduction in hepatic DAG by ATGL deficiency likely directly stems from defective TAG lipolysis to DAG in hepatocytes.…”