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The Causative Gene in Chanarian Dorfman Syndrome Regulates Lipid Droplet Homeostasis in C. elegans.

Xie M, Roy R - PLoS Genet. (2015)

Bottom Line: We found that the compromise of one of the three C. elegans orthologues of human cgi-58 significantly improves the survival of AMPK-deficient dauers.We also provide evidence that C. elegans CGI-58 acts as a co-activator of ATGL-1, while it also functions cooperatively to maintain regular lipid droplet structure.Surprisingly, we show that it also acts independently of ATGL-1 to restrict lipid droplet coalescence by altering the surface abundance and composition of long chain (C20) polyunsaturated fatty acids (PUFAs).

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, McGill University, Penfield, Montreal, Quebec, Canada.

ABSTRACT
AMP-activated kinase (AMPK) is a key regulator of many cellular mechanisms required for adjustment to various stresses induced by the changing environment. In C. elegans dauer larvae AMPK- mutants expire prematurely due to hyperactive Adipose Triglyceride Lipase (ATGL-1) followed by rapid depletion of triglyceride stores. We found that the compromise of one of the three C. elegans orthologues of human cgi-58 significantly improves the survival of AMPK-deficient dauers. We also provide evidence that C. elegans CGI-58 acts as a co-activator of ATGL-1, while it also functions cooperatively to maintain regular lipid droplet structure. Surprisingly, we show that it also acts independently of ATGL-1 to restrict lipid droplet coalescence by altering the surface abundance and composition of long chain (C20) polyunsaturated fatty acids (PUFAs). Our data reveal a novel structural role of CGI-58 in maintaining lipid droplet homeostasis through its effects on droplet composition, morphology and lipid hydrolysis; a conserved function that may account for some of the ATGL-1-independent features unique to Chanarin-Dorfman Syndrome.

No MeSH data available.


Related in: MedlinePlus

Dietary C20PUFA supplementation reduced the number of lipid droplet aggregates in CGI-58 and AMPK; CGI-58 mutants.(A)-(B) Dietary supplementation of C20PUFA enriched the lipid droplet C20PUFA composition of daf-2; aak(0); cgi-58(A) and daf-2; cgi-58(B) dauer larvae represented by their increased C20PUFA portion. (C) Less lipid droplet aggregates were observed in both the daf-2; cgi-58 and daf-2; aak(0); cgi-58 animals following C20PUFA dietary supplementation. Lipid droplets with a volume greater than 20 μm3 are considered as aggregates.
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pgen.1005284.g007: Dietary C20PUFA supplementation reduced the number of lipid droplet aggregates in CGI-58 and AMPK; CGI-58 mutants.(A)-(B) Dietary supplementation of C20PUFA enriched the lipid droplet C20PUFA composition of daf-2; aak(0); cgi-58(A) and daf-2; cgi-58(B) dauer larvae represented by their increased C20PUFA portion. (C) Less lipid droplet aggregates were observed in both the daf-2; cgi-58 and daf-2; aak(0); cgi-58 animals following C20PUFA dietary supplementation. Lipid droplets with a volume greater than 20 μm3 are considered as aggregates.

Mentions: If indeed the reduced C20PUFA composition of the lipid droplet contributes to the coalescence behaviours that we observe in the AMPK mutant animals that lack CGI-58 then increasing their concentration should improve the defect in the mutant lipid droplets. We therefore supplemented the food with C20PUFAs and fed this mixture to both animals that lacked CGI-58 and those that were mutant for both AMPK and CGI-58. The supplementation successfully enriched the C20PUFA concentration in the lipid droplets isolated from both groups (Fig 7A and 7B), and which led to a reduced number of lipid droplet aggregates in these animals (Fig 7C). These results suggest that in C. elegans CGI-58 is essential to maintain the abundance of certain fatty acid species in both the triglyceride (C18s) and phospholipid (C20PUFAs) compartments, where the former serve as precursors for the latter. Because the composition of long chain fatty acids present on the lipid droplet surface can affect numerous physical parameters of the organelle including the intrinsic curvature of connected lipid droplets that determines further expansion or closure of the connected pores [24], it is not inconceivable that the effects of C. elegans CGI-58 impinge on lipid composition of the droplet monolayer, which indirectly blocks droplet fusion in AMPK mutant dauer larvae.


The Causative Gene in Chanarian Dorfman Syndrome Regulates Lipid Droplet Homeostasis in C. elegans.

Xie M, Roy R - PLoS Genet. (2015)

Dietary C20PUFA supplementation reduced the number of lipid droplet aggregates in CGI-58 and AMPK; CGI-58 mutants.(A)-(B) Dietary supplementation of C20PUFA enriched the lipid droplet C20PUFA composition of daf-2; aak(0); cgi-58(A) and daf-2; cgi-58(B) dauer larvae represented by their increased C20PUFA portion. (C) Less lipid droplet aggregates were observed in both the daf-2; cgi-58 and daf-2; aak(0); cgi-58 animals following C20PUFA dietary supplementation. Lipid droplets with a volume greater than 20 μm3 are considered as aggregates.
© Copyright Policy
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4470697&req=5

pgen.1005284.g007: Dietary C20PUFA supplementation reduced the number of lipid droplet aggregates in CGI-58 and AMPK; CGI-58 mutants.(A)-(B) Dietary supplementation of C20PUFA enriched the lipid droplet C20PUFA composition of daf-2; aak(0); cgi-58(A) and daf-2; cgi-58(B) dauer larvae represented by their increased C20PUFA portion. (C) Less lipid droplet aggregates were observed in both the daf-2; cgi-58 and daf-2; aak(0); cgi-58 animals following C20PUFA dietary supplementation. Lipid droplets with a volume greater than 20 μm3 are considered as aggregates.
Mentions: If indeed the reduced C20PUFA composition of the lipid droplet contributes to the coalescence behaviours that we observe in the AMPK mutant animals that lack CGI-58 then increasing their concentration should improve the defect in the mutant lipid droplets. We therefore supplemented the food with C20PUFAs and fed this mixture to both animals that lacked CGI-58 and those that were mutant for both AMPK and CGI-58. The supplementation successfully enriched the C20PUFA concentration in the lipid droplets isolated from both groups (Fig 7A and 7B), and which led to a reduced number of lipid droplet aggregates in these animals (Fig 7C). These results suggest that in C. elegans CGI-58 is essential to maintain the abundance of certain fatty acid species in both the triglyceride (C18s) and phospholipid (C20PUFAs) compartments, where the former serve as precursors for the latter. Because the composition of long chain fatty acids present on the lipid droplet surface can affect numerous physical parameters of the organelle including the intrinsic curvature of connected lipid droplets that determines further expansion or closure of the connected pores [24], it is not inconceivable that the effects of C. elegans CGI-58 impinge on lipid composition of the droplet monolayer, which indirectly blocks droplet fusion in AMPK mutant dauer larvae.

Bottom Line: We found that the compromise of one of the three C. elegans orthologues of human cgi-58 significantly improves the survival of AMPK-deficient dauers.We also provide evidence that C. elegans CGI-58 acts as a co-activator of ATGL-1, while it also functions cooperatively to maintain regular lipid droplet structure.Surprisingly, we show that it also acts independently of ATGL-1 to restrict lipid droplet coalescence by altering the surface abundance and composition of long chain (C20) polyunsaturated fatty acids (PUFAs).

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, McGill University, Penfield, Montreal, Quebec, Canada.

ABSTRACT
AMP-activated kinase (AMPK) is a key regulator of many cellular mechanisms required for adjustment to various stresses induced by the changing environment. In C. elegans dauer larvae AMPK- mutants expire prematurely due to hyperactive Adipose Triglyceride Lipase (ATGL-1) followed by rapid depletion of triglyceride stores. We found that the compromise of one of the three C. elegans orthologues of human cgi-58 significantly improves the survival of AMPK-deficient dauers. We also provide evidence that C. elegans CGI-58 acts as a co-activator of ATGL-1, while it also functions cooperatively to maintain regular lipid droplet structure. Surprisingly, we show that it also acts independently of ATGL-1 to restrict lipid droplet coalescence by altering the surface abundance and composition of long chain (C20) polyunsaturated fatty acids (PUFAs). Our data reveal a novel structural role of CGI-58 in maintaining lipid droplet homeostasis through its effects on droplet composition, morphology and lipid hydrolysis; a conserved function that may account for some of the ATGL-1-independent features unique to Chanarin-Dorfman Syndrome.

No MeSH data available.


Related in: MedlinePlus