Z Gastroenterol 2020; 58(01): e24
DOI: 10.1055/s-0039-3402164
Poster Visit Session III Metabolism (incl. NAFLD): Friday, February 14, 2020, 4:40 pm – 5:25 pm, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

Lipid droplet proteins in alcoholic and non-alcoholic steatohepatitis in patients with polymorphisms in PNPLA3

HR Witzel
1   University Medical Center Mainz, Institute of Pathology, Mainz, Germany
,
I Schwittai
1   University Medical Center Mainz, Institute of Pathology, Mainz, Germany
,
LM Pawella
2   University Medical Center Heidelberg, Institute of Pathology, Heidelberg, Germany
,
V Rausch
3   Salem Medical Center, Department of Internal Medicine, Heidelberg, Germany
,
S Mueller
3   Salem Medical Center, Department of Internal Medicine, Heidelberg, Germany
,
J Schattenberg
4   University Medical Center Mainz, Department of Internal Medicine, Mainz, Germany
,
N Hartmann
1   University Medical Center Mainz, Institute of Pathology, Mainz, Germany
,
P Schirmacher
2   University Medical Center Heidelberg, Institute of Pathology, Heidelberg, Germany
,
W Roth
1   University Medical Center Mainz, Institute of Pathology, Mainz, Germany
,
BK Straub
1   University Medical Center Mainz, Institute of Pathology, Mainz, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

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Question:

Lipid droplets (LDs) are crucial organelles that play a central role in lipid homeostasis. A particular lipase associated with LDs is the patatin-like phospholipase domain containing protein 3 (PNPLA3). The I148 M single nucleotide polymorphism of PNPLA3 has been shown to be associated with non-alcoholic fatty liver disease and the development of hepatocellular carcinoma. Aim of the study was to investigate the underlying molecular mechanism driving the progression of the disease.

Methods:

To unravel the interplay between PNPLA3 and the LD-associated proteins of the perilipin-family in the regulation of LDs, (immuno)-histochemical analysis of a collective of 47 ASH- and 25 NASH-patients with known PNPLA3-status was undertaken. In addition, co-immunoprecipitation experiments were performed to identify novel PNPLA3 binding partners. Finally, the impact of the polymorphism on the lipolytic activity was determined.

Results:

Histologically, livers of I148 M carriers showed enhanced ballooning, acinar inflammation, microgranulomas and increased fibrosis with a prominent staining for perilipin 2 at ballooned hepatocytes. Perilipin 5 localized less to LDs, but showed a more cytoplasmic and partially nuclear localization instead. Interestingly, hepatocytes that were strongly positive for PNPLA3 showed diminished perilipin 1-expression.

Furthermore, we identified perilipin 5 and the lipase PNPLA2/ATGL as novel interaction partners of PNPLA3 that co-localized at LDs. In addition, we could show that perilipin 5, PNPLA3, and PNPLA2 are part of the same complex and that perilipin 5 is enhancing the binding of PNPLA3 with PNPLA2 dramatically. Strikingly, we could show dimerization of PNPLA2, a process inhibited by PNPLA3. Addressing the lipolytic activity of PNPLA2 revealed an inhibitory effect of PNPLA3, which is strongest for PNPLA3(I148 M).

Conclusion:

In summary, our data indicate that PNPLA3 regulates lipolysis by repressing the lipolytic activity of PNPLA2 in a perilipin 5-dependent manner most likely via disrupting active PNPLA2 homo-dimers/oligomers. The enzymatically inactive PNPLA3(I148 M) even further reduces PNPLA2-mediated lipolysis and increases toxic accumulation of lipids. We have thereby unraveled a mechanism of PNPLA3 in the progression of steatotic liver diseases. Concerning the long-standing debate on why and when bland steatosis progresses to steato-hepatitis, our data point to a critical step in lipolysis rather than in lipogenesis itself.