PNPLA3(I148M) Inhibits Lipolysis by Perilipin-5-Dependent Competition with ATGL

Hagen Roland Witzel; Inga Maria Gertrud Schwittai; Nils Hartmann; Sebastian Mueller; Jörn M Schattenberg; Xue-Min Gong; Johannes Backs; Peter Schirmacher; Detlef Schuppan; Wilfried Roth; Beate Katharina Straub

doi:10.3390/cells12010073

PNPLA3(I148M) Inhibits Lipolysis by Perilipin-5-Dependent Competition with ATGL

Cells. 2022 Dec 24;12(1):73. doi: 10.3390/cells12010073.

Affiliations

¹ Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany.
² Department of Internal Medicine, Salem Medical Center, 69121 Heidelberg, Germany.
³ Metabolic Liver Research Program, I. Department of Medicine, University Medical Center, 55131 Mainz, Germany.
⁴ Institute of Experimental Cardiology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
⁵ Institute of Pathology, University Medical Center Heidelberg, 69120 Heidelberg, Germany.
⁶ Translational Immunology, Research Center for Immune Therapy, University Medicine Mainz, 55131 Mainz, Germany.
⁷ Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.

Abstract

The single nucleotide polymorphism I148M of the lipase patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an unfavorable prognosis in alcoholic and non-alcoholic steatohepatitis (ASH, NASH), with progression to liver cirrhosis and development of hepatocellular carcinoma. In this study, we investigated the mechanistic interaction of PNPLA3 with lipid droplet (LD)-associated proteins of the perilipin family, which serve as gatekeepers for LD degradation. In a collective of 106 NASH, ASH and control liver samples, immunohistochemical analyses revealed increased ballooning, inflammation and fibrosis, as well as an accumulation of PNPLA3-perilipin 5 complexes on larger LDs in patients homo- and heterozygous for PNPLA3(I148M). Co-immunoprecipitation demonstrated an interaction of PNPLA3 with perilipin 5 and the key enzyme of lipolysis, adipose triglyceride lipase (ATGL). Localization studies in cell cultures and human liver showed colocalization of perilipin 5, ATGL and PNPLA3. Moreover, the lipolytic activity of ATGL was negatively regulated by PNPLA3 and perilipin 5, whereas perilipin 1 displaced PNPLA3 from the ATGL complex. Furthermore, ballooned hepatocytes, the hallmark of steatohepatitis, were positive for PNPLA3 and perilipins 2 and 5, but showed decreased perilipin 1 expression with respect to neighboured hepatocytes. In summary, PNPLA3- and ATGL-driven lipolysis is significantly regulated by perilipin 1 and 5 in steatohepatitis.

Keywords: NAFLD; PNPLA3; alcoholic steatohepatitis (ASH); ballooned hepatocytes; lipid droplets; lipoloysis; non-alcoholic steatohepatitis (NASH); perilipin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Lipolysis
Liver Neoplasms*
Non-alcoholic Fatty Liver Disease* / genetics
Non-alcoholic Fatty Liver Disease* / pathology
Perilipin-1
Perilipin-5

Substances

Perilipin-1
Perilipin-5
PNPLA2 protein, human

Grants and funding

This research was funded by grants of the German Research Foundation to BKS (DFG, STR1160/1-1 as well as 1-2). DS and JMS have received project related support by the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) consortium funded by the Innovative Medicines Initiative (IMI2) Program of the European Union under Grant Agreement 777377.