Potential mechanism underlying the PNPLA3(I) (148) (M) -Hepatic steatosis connection.

Abstract

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: Smagris et al.1 elegantly show that knock‐in mice homozygous for the PNPLA3148M variant of adiponutrin develop hepatic steatosis when fed a high‐sucrose diet, reproducing the strongest known genetic association with hepatic steatosis in humans. PNPLA3148M knock‐in mice provide a powerful tool for exploring the mechanisms of hepatic steatosis. One plausible and testable mechanism involves the dynamic interactions among lipases and other lipid droplet (LD) surface proteins. Potentially, PNPLA3148M may compete with ATGL (PNPLA2, the major hepatic triglyceride lipase) for CGI‐58 binding (Fig. 1), leading to the reduced lipolytic capacity, steatosis and increase of large LDs observed in PNPLA3148M knock‐in livers.Figure 1: Schematic drawing of hepatic LD surface lipolysis regulated by interactions between lipase and LD surface proteins. Left, normal liver (PNPLA3148I). Upon lipolytic stimulation, the hepatic LD surface protein, PLIN5, releases CGI‐58, which binds to ATGL and enhances lipolysis. Right, PNPLA3148M knock‐in liver. CGI‐58 binding to PNPLA3 reduces CGI‐58 binding to ATGL, decreasing lipolytic activity and leading to bigger LDs. Despite the presence of equal amounts of total ATGL, CGI‐58, and PLIN‐5, as observed by Smagris et al., protein interactions and lipolytic activity differ markedly between normal and knock‐in livers.Several observations are consistent with this hypothesis. The investigators show that PNPLA3148M accumulates on the LD surface in knock‐in livers, in contrast to wild‐type PNPLA3148I, which is barely detectable on normal liver LDs. Therefore, ATGL and PNPLA3148M are both present on the LD surface. Also, ATGL and PNPLA3 share the highest homology of any patatin domain proteins.2 Binding of ATGL to CGI‐58 is well documented,3 and PNPLA3148M also colocalizes with CGI‐58.4 CGI‐58 is felt to decrease liver fat content by binding to and activating ATGL and hence by increasing lipolysis. Conversely, CGI‐58 deficiency is known to produce hepatic steatosis.5 Although Smagris et al. found that total CGI‐58 levels did not correlate with severity of hepatic steatosis, competition for CGI‐58 binding between ATGL and PNPLA3148M may reduce the ATGL‐bound fraction of CGI‐58 in PNPLA3148M knock‐in livers, inhibiting lipolysis and resulting in hepatic steatosis. Although more‐complex mechanisms may be responsible for PNPLA3148M‐associated hepatic steatosis, this simple hypothesis is testable in PNPLA3I148M knock‐in and control livers by performing immunofluorescent colocalization and coimmunoprecipitation experiments for all combinations of PNPLA3, ATGL, and CGI‐58.