We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
PNPLA3(I148M) Inhibits Lipolysis by Perilipin-5-Dependent Competition with ATGL.
- Authors
Witzel, Hagen Roland; Schwittai, Inga Maria Gertrud; Hartmann, Nils; Mueller, Sebastian; Schattenberg, Jörn M.; Gong, Xue-Min; Backs, Johannes; Schirmacher, Peter; Schuppan, Detlef; Roth, Wilfried; Straub, Beate Katharina
- 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.
- Subjects
PHOSPHOLIPASES; LIPOLYSIS; NON-alcoholic fatty liver disease; SINGLE nucleotide polymorphisms; HUMAN cell culture; PERILIPIN; IMMUNOHISTOCHEMISTRY
- Publication
Cells (2073-4409), 2023, Vol 12, Issue 1, p73
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells12010073