Balancing the fat: Dynamic interactions of ABHD5 with PNPLA3 in the regulation of triacylglycerol metabolism

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Date: January 22, 2020
Time: 4:00 p.m. - 5:00 p.m.
Location: Biological Sciences #1167 | Map
5047 Gullen Mall
Detroit, MI 48202
Category: Seminar

Balancing the fat:  Dynamic interactions of ABHD5 with PNPLA3 in the regulation of triacylglycerol metabolism

Alexander Yang, MD/Ph.D. candidate
Molecular Medicine and Genetics 
Wayne State University


The storage and mobilization of intracellular triacylglycerol (TG) are critical functions of adipose tissue and liver, and disruption of these processes can lead to metabolic diseases, including diabetes and fatty liver disease. PNPLA2 (also known as adipose triglyceride lipase and desnutrin) and PNPLA3 (also known as adiponutrin) are close paralogs that are oppositely regulated under physiological conditions that promote lipolysis or lipogenesis.  PNPLA2 is well established as a critical TG lipase in adipose tissue and liver whose expression is upregulated by fasting, in part by the transcription factor Foxo1.  In contrast, PNPLA3 expression is induced by feeding and is under the control of the lipogenic transcription factors SREBP1 and ChREBP.  Although these observations strongly suggest that PNPLA3 is involved in promoting TG accumulation, the mechanisms involved remain unclear and controversial.  Given the evolution histories of PNPLA paralogs, we hypothesized that PNPLA3 would bind ABHD5 but not activate lipolysis. If so, then upregulation of PNPLA3 might sequester ABHD5 from PNPLA2 and thereby suppress lipolysis. 

We report that PNPLA3 strongly interacts with ABHD5 in molecular imaging, protein complementation, and immunoprecipitation assays. The interaction between ABHD5 and PNPLA3 occurs mainly on ER-like structures and is promoted when cells are exposed to oleic acid, which generates ABHD5 ligands and increases TG storage.  Importantly, the I148M PNPLA3 variant, which promotes TG accumulation in humans and mice, exhibits greater interaction with ABHD5 in transfected cells. Interestingly, the interaction of ABHD5 with I148M PNPLA3 occurs mainly on expanded lipid droplet structures.  We next tested whether PNPLA2 and PNPLA3 paralogs compete for ABHD5 and if such competition reduces ATGL/PNPLA2-dependent lipolysis. We found that overexpression of PNPLA3 suppressed the interaction of ABHD5 and PNPLA2 in bimolecular fluorescence complementation assays. The I148M PNPLA3 variant was more effective in inhibiting the interaction of ABHD5 and PNPLA2, perhaps owing to its greater stability and targeting to lipid droplets. Using cultured brown adipocytes as a model system, we found that doxycycline-inducible expression of wild type (WT) PNPLA3 or the I148M variant suppressed lipolysis induced by pharmacological activation of b-adrenergic receptors or ABHD5.  The conserved interaction of PNPLA3 and PNPLA2 with ABHD5 provides a clear molecular and physiological mechanism for suppressing lipolysis during the fast to fed transition.  Furthermore, the greater functional interaction of ABHD5 with I148M PNPLA3 might explain its ability to act as a gain of function variant with respect to hepatic TG accumulation. Lastly, our results strongly imply the presence of lipase-independent, activities of the ABHD5/PNPLA3 interaction in metabolic tissues, which are now under investigation. 


Jiajia Ji