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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. [ABSTRACT FROM AUTHOR]

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.

Niemann-Pick type C (NPC) disease is a fatal inherited neurodegenerative disorder caused by loss-of-function mutations in the NPC1 or NPC2 gene. There is no effective way to treat NPC disease. In this study, we used adeno-associated virus (AAV) serotype 9 (AAV9) to deliver a functional NPC1 gene systemically into NPC1 -/- mice at postnatal day 4. One single AAV9-NPC1 injection resulted in robust NPC1 expression in various tissues, including brain, heart, and lung. Strikingly, AAV9-mediated NPC1 delivery significantly promoted Purkinje cell survival, restored locomotor activity and coordination, and increased the lifespan of NPC1 -/- mice. Our work suggests that AAV-based gene therapy is a promising means to treat NPC disease., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)