ATGL/CGI-58-Dependent Hydrolysis of a Lipid Storage Pool in Murine Enterocytes

Korbelius, Melanie; Vujić, Nemanja; Sachdev, Vinay; Obrowsky, Sascha; Rainer, Silvia; Gottschalk, Benjamin; Graier, Wolfgang F.; Kratky, Dagmar

doi:10.1016/j.celrep.2019.07.030

Cited by 33 publications

(57 citation statements)

References 51 publications

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“…As we have reliably enriched ATGL from other cells and tissues employing the same activity-based approach, this finding indicates low expression levels and/or activity of ATGL in the small intestine. This is in line with recent results showing that ATGL/ABHD5 deletion does not affect luminal lipid absorption or CM secretion of enterocytes ( 14 ). Despite its significant enrichment in jejunum and ileum, HSL has already been ruled out as a bulk TAG hydrolase in enterocytes ( 13 ).…”

Section: Discussionsupporting

confidence: 93%

“…A recent study utilizing intestine specific double knock-out mice lacking both, ATGL and its activator alpha/beta hydrolase domain-containing protein 5 (ABHD5 alias CGI-58, Q9DBL9, Abhd5), showed prominent accumulation of TAG in the proximal parts of the small intestine 14 . However, the same study revealed that this TAG originates from the basolateral side of the enterocyte and not from dietary lipids.…”

Section: Introductionmentioning

confidence: 99%

“…Likewise, targeted disruption of hormone sensitive lipase (HSL, P54310, Lipe ) expression in murine enterocytes ( 13 ) only influences plasma cholesterol but not plasma TAG or enterocyte TAG levels. A recent study utilizing intestine specific double knock-out mice lacking both, ATGL and its activator alpha/beta hydrolase domain-containing protein 5 (ABHD5 alias CGI-58, Q9DBL9, Abhd5 ), showed prominent accumulation of TAG in the proximal parts of the small intestine ( 14 ). However, the same study revealed that this TAG originates from the basolateral side of the enterocyte and not from dietary lipids.…”

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confidence: 99%

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Spatially Resolved Activity-based Proteomic Profiles of the Murine Small Intestinal Lipases

Schittmayer

Vujić

Darnhofer

et al. 2020

Molecular & Cellular Proteomics

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Despite the crucial function of the small intestine in nutrient uptake our understanding of the molecular events underlying the digestive function is still rudimentary. Recent studies demonstrated that enterocytes do not direct the entire dietary triacylglycerol toward immediate chylomicron synthesis. Especially after high-fat challenges, parts of the resynthesized triacylglycerol are packaged into cytosolic lipid droplets for transient storage in the endothelial layer of the small intestine. The reason for this temporary storage of triacylglycerol is not completely understood. To utilize lipids from cytosolic lipid droplets for chylomicron synthesis in the endoplasmic reticulum, stored triacylglycerol has to be hydrolyzed either by cytosolic lipolysis or lipophagy. Interestingly, triacylglycerol storage and chylomicron secretion rates are unevenly distributed along the small intestine, with the proximal jejunum exhibiting the highest intermittent storage capacity. We hypothesize that correlating hydrolytic enzyme activities with the reported distribution of triacylglycerol storage and chylomicron secretion in different sections of the small intestine is a promising strategy to determine key enzymes in triacylglycerol remobilization. We employed a serine hydrolase specific activity-based labeling approach in combination with quantitative proteomics to identify and rank hydrolases based on their relative activity in 11 sections of the small intestine. Moreover, we identified several clusters of enzymes showing similar activity distribution along the small intestine. Merging our activity-based results with substrate specificity and subcellular localization known from previous studies, carboxylesterase 2e and arylacetamide deacetylase emerge as promising candidates for triacylglycerol mobilization from cytosolic lipid droplets in enterocytes.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Spatially Resolved Activity-based Proteomic Profiles of the Murine Small Intestinal Lipases

Schittmayer

Vujić

Darnhofer

et al. 2020

Molecular & Cellular Proteomics

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“…However, if ATGL plays an important role in the hepatic lipid droplet degradation, the degraded triglycerides seem to be channelled towards fatty acid oxidation rather than VLDL-dependent triglyceride secretion [62,63]. Interestingly, in the intestine, ABHD5 and ATGL also participate in lipid droplet degradation but not in chylomicron synthesis as their double knockout in the small intestine of mice does not affect plasma triglyceride levels [66]. Our results confirmed the role of ATGL in lipid droplet degradation in liverderived cells.…”

Section: Plos Pathogenssupporting

confidence: 77%

The ATGL lipase cooperates with ABHD5 to mobilize lipids for hepatitis C virus assembly

et al. 2020

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Lipid droplets are essential cellular organelles for storage of fatty acids and triglycerides. The hepatitis C virus (HCV) translocates several of its proteins onto their surface and uses them for production of infectious progeny. We recently reported that the lipid droplet-associated α/β hydrolase domain-containing protein 5 (ABHD5/CGI-58) participates in HCV assembly by mobilizing lipid droplet-associated lipids. However, ABHD5 itself has no lipase activity and it remained unclear how ABHD5 mediates lipolysis critical for HCV assembly. Here, we identify adipose triglyceride lipase (ATGL) as ABHD5 effector and new host factor involved in the hepatic lipid droplet degradation as well as in HCV and lipoprotein morphogenesis. Modulation of ATGL protein expression and lipase activity controlled lipid droplet lipolysis and virus production. ABHD4 is a paralog of ABHD5 unable to activate ATGL or support HCV assembly and lipid droplet lipolysis. Grafting ABHD5 residues critical for activation of ATGL onto ABHD4 restored the interaction between lipase and co-lipase and bestowed the pro-viral and lipolytic functions onto the engineered protein. Congruently, mutation of the predicted ABHD5 protein interface to ATGL ablated ABHD5 functions in lipid droplet lipolysis and HCV assembly. Interestingly, minor alleles of ABHD5 and ATGL associated with neutral lipid storage diseases in human, are also impaired in lipid droplet lipolysis and their pro-viral functions. Collectively, these results show that ABHD5 cooperates with ATGL to mobilize triglycerides for HCV infectious virus production. Moreover, viral manipulation of lipid droplet homeostasis via the ABHD5-ATGL axis, akin to natural genetic variation in these proteins, emerges as a possible mechanism by which chronic HCV infection causes liver steatosis.

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“…Mice were sacrificed 4 h post-gavage and lipid concentrations in duodenum, jejunum, and ileum were estimated [ 18 ]. Histologic sections of the small intestine and oil red O (ORO) staining were performed as described [ 19 ].…”

Section: Methodsmentioning

confidence: 99%

Intestine-specific DGAT1 deficiency improves atherosclerosis in apolipoprotein E knockout mice by reducing systemic cholesterol burden

et al. 2020

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Background and aims Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is the rate-limiting enzyme catalyzing the final step of triglyceride synthesis by esterifying a diglyceride with a fatty acid. We have previously shown that apolipoprotein E-knockout ( ApoE −/− ) mice lacking Dgat1 have reduced intestinal cholesterol absorption and potentiated macrophage cholesterol efflux, and consequently, exhibit attenuated atherogenesis. However, he-matopoietic Dgat1 deficiency lacked beneficial effects on atherosclerosis. Due to our recent results on the critical role of intestinal Dgat1 in murine cholesterol homeostasis, we delineated whether intestinal Dgat1 deficiency regulates atherogenesis in mice. Methods We generated intestine-specific Dgat1 −/− mice on the ApoE −/− background ( iDgat1 −/− ApoE −/− ) and determined cholesterol homeostasis and atherosclerosis development. Results When fed a Western-type diet, iDgat1 −/− ApoE −/− mice exhibited a substantial decrease in fasting plasma cholesterol content in ApoB-containing lipoproteins. Although lipid absorption was delayed, iDgat1 −/− ApoE −/− mice had reduced acute and fractional cholesterol absorption coupled with an elevated fecal caloric loss. In line, increased appearance of i.v. administered [3H]cholesterol in duodena and stool of iDgat1 −/− ApoE −/− animals suggested potentiated cholesterol elimination. Atherosclerotic lesions were markedly smaller with beneficial alterations in plaque composition as evidenced by reduced macrophage infiltration and necrotic core size despite unaltered collagen content, indicating improved plaque stability. Conclusions Disruption of Dgat1 activity solely in the small intestine of ApoE −/− mice strongly decreased plasma cholesterol levels by abrogating the assimilation of dietary cholesterol, partly by reduced absorption and increased excretion. Consequently, the reduced cholesterol burden significantly attenuated atherogenesis and improved the lesion phenotype in iDgat1 −/− ApoE −/− mice.

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ATGL/CGI-58-Dependent Hydrolysis of a Lipid Storage Pool in Murine Enterocytes

Cited by 33 publications

References 51 publications

Spatially Resolved Activity-based Proteomic Profiles of the Murine Small Intestinal Lipases

Spatially Resolved Activity-based Proteomic Profiles of the Murine Small Intestinal Lipases

The ATGL lipase cooperates with ABHD5 to mobilize lipids for hepatitis C virus assembly

Intestine-specific DGAT1 deficiency improves atherosclerosis in apolipoprotein E knockout mice by reducing systemic cholesterol burden

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