ABHD5 Enzymatic Function and Role in Lipolysis

PROJECT SUMMARY / ABSTRACT
This proposal aims to determine the function of ABHD5, a protein that is essential for the
catabolism of triacylglycerol in humans, as well as in other animals, worms, and plants. Loss of
function mutations in, or deletion of, ABHD5 blocks the hydrolysis of triacylglycerol, which
accumulates, and leads to ichthyosis, steatosis, myopathy, and other alterations. ABHD5 has
been reported to activate two enzymes: ATGL, the main triacylglycerol lipase in cells, and
PNPLA1, which catalyzes the synthesis of acylceramides in skin. In addition, ABHD5 has been
proposed to regulate ATGL activity and thus, triacylglycerol lipolysis and storage in cells.
However, the mechanism of action of ABHD5 remains undefined. Moreover, several lines of
evidence suggest that ABHD5 is not a direct activator of ATGL: We have shown that
overexpression of ABHD5 in mouse adipose tissue, which expresses high levels of ATGL, does
not increase lipolysis. In addition, in ATGL knock-out mice, simultaneous knock-down of ABHD5
increases liver TAG further, indicating that even in the absence of ATGL, ABHD5 regulates TAG
amounts, thus implying a mechanism independent of ATGL. This suggests that ABHD5 does
not directly activate ATGL, but rather that ABHD5 catalyzes a different reaction in triacylglycerol
lipolysis.
This project proposes to conduct enzymology studies using purified ABHD5, ATGL, and
catalytically dead mutant forms, to determine the enzymatic function of ABHD5, its substrates
and products, and the regulation ATGL. In addition, it proposes lipidology studies to show how
the proposed ABHD5 function explains the lipid alterations described in cells lacking functional
ABHD5.
These studies are expected to elucidate the function of ABHD5, refine the understanding of the
enzymatic reactions in the lipolytic pathway, and shed light on its regulation. This new
knowledge will change the current understanding of lipolysis and provide new insights into
obesity and related diseases.
This research will be conducted by a team composed primarily of undergraduate students. It will
allow the students to gain experience in biomedical research, support research by the principal
investigator, and promote collaborations that will strengthen the research environment at
Brooklyn College.

Grant Number: 1R15DK131627-01
NIH Institute/Center: NIH
Principal Investigator: Jorge Caviglia