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CGI-58/ABHD5-Derived Signaling Lipids Regulate Systemic Inflammation and Insulin Action

Lord, Caleb C., Betters, Jenna L., Ivanova, Pavlina T., Milne, Stephen B., Myers, David S., Madenspacher, Jennifer, Thomas, Gwynneth, Chung, Soonkyu, Liu, Mingxia, Davis, Matthew A., Lee, Richard G., Crooke, Rosanne M., Graham, Mark J., Parks, John S., Brasaemle, Dawn L., Fessler, Michael B., Brown, H. Alex, Brown, J. Mark·2012·Diabetes
DOI 10.2337/db11-0994PMC PMC3266405
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Abstract

Mutations of comparative gene identification 58 (CGI-58) in humans cause Chanarin-Dorfman syndrome, a rare autosomal recessive disease in which excess triacylglycerol (TAG) accumulates in multiple tissues. CGI-58 recently has been ascribed two distinct biochemical activities, including coactivation of adipose triglyceride lipase and acylation of lysophosphatidic acid (LPA). It is noteworthy that both the substrate (LPA) and the product (phosphatidic acid) of the LPA acyltransferase reaction are well-known signaling lipids. Therefore, we hypothesized that CGI-58 is involved in generating lipid mediators that regulate TAG metabolism and insulin sensitivity. Here, we show that CGI-58 is required for the generation of signaling lipids in response to inflammatory stimuli and that lipid second messengers generated by CGI-58 play a critical role in maintaining the balance between inflammation and insulin action. Furthermore, we show that CGI-58 is necessary for maximal TH1 cytokine signaling in the liver. This novel role for CGI-58 in cytokine signaling may explain why diminished CGI-58 expression causes severe hepatic lipid accumulation yet paradoxically improves hepatic insulin action. Collectively, these findings establish that CGI-58 provides a novel source of signaling lipids. These findings contribute insight into the basic mechanisms linking TH1 cytokine signaling to nutrient metabolism.

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FIG. 1. CGI-58 KD dissociates hepatic steatosis from insulin resistance. A: Photographs depicting hepatic steatosis and adiposity in C57BL/6N mice fed either a chow or HFD for 10 weeks in conjunction with biweekly injections (25 mg/kg) of either a nontargeting control ASO or ASO targeting KD of CGI-58 (CGI-58 ASO). B–G: Despite hepatic lipid insult, KD of CGI-58 enhances insulin signaling. Mice were fed either a chow or HFD and treated with ASOs for 8 weeks. Mice were fasted for 10 h before saline or insulin injection into the portal vein. Exactly 5 min later, tissues were excised and immediately snap-frozen in liquid nitrogen. Protein extracts from the liver (B), skeletal muscle (C), and adipose tissue (D) were analyzed by Western blotting for total Akt, phospho (p)-Akt (Ser473 and Thr308), and phospho (p)-FoxO1 (Ser256); three representative animals are shown for each group. E–G: Densitometric analyses of insulin signaling: Phospho-Akt protein levels were normalized to total Akt in liver (E), skeletal muscle (F), and adipose tissue (G). □, control ASO; ■, CGI-58 ASO. Data represent the mean ± SEM from three mice per group, and values not sharing a common superscript letter differ significantly (P < 0.05). AU, arbitrary unit. (A high-quality digital representation of this figure is available in the online issue.)
FIG. 1. CGI-58 KD dissociates hepatic steatosis from insulin resistance. A: Photographs depicting hepatic steatosis and adiposity in C57BL/6N mice fed either a chow or HFD for 10 weeks in conjunction with biweekly injections (25 mg/kg) of either a nontargeting control ASO or ASO targeting KD of CGI-58 (CGI-58 ASO). B–G: Despite hepatic lipid insult, KD of CGI-58 enhances insulin signaling. Mice were fed either a chow or HFD and treated with ASOs for 8 weeks. Mice were fasted for 10 h before saline or insulin injection into the portal vein. Exactly 5 min later, tissues were excised and immediately snap-frozen in liquid nitrogen. Protein extracts from the liver (B), skeletal muscle (C), and adipose tissue (D) were analyzed by Western blotting for total Akt, phospho (p)-Akt (Ser473 and Thr308), and phospho (p)-FoxO1 (Ser256); three representative animals are shown for each group. E–G: Densitometric analyses of insulin signaling: Phospho-Akt protein levels were normalized to total Akt in liver (E), skeletal muscle (F), and adipose tissue (G). □, control ASO; ■, CGI-58 ASO. Data represent the mean ± SEM from three mice per group, and values not sharing a common superscript letter differ significantly (P < 0.05). AU, arbitrary unit. (A high-quality digital representation of this figure is available in the online issue.)CC BY-NC-ND · PubMed Central
FIG. 2. CGI-58 KD alters HFD-induced inflammation: Evidence of hepatic cytokine resistance. C57BL/6N mice were fed either a standard chow or HFD in conjunction with biweekly injections of either a nontargeting control ASO (□) or ASO targeting KD of CGI-58 (CGI-58 ASO; ■) for 10 weeks. A: Plasma levels of proinflammatory cytokines, including IL-6 and IL-12p40; monocyte chemoattractant protein-1 (MCP-1); macrophage inflammatory protein-2 (MIP-2); CXCL1 (KC); and regulated upon activation, normal T-cell expressed, and RANTES. Data represent the mean ± SEM from five mice per group, and values not sharing a common superscript letter differ significantly (P < 0.05). ND, levels below limit of detection. B and C: HFD-induced stress kinase activation. Representative immunoblots from liver (B) or epididymal adipose tissue (C) are shown for phospho-IκB kinase α/β (p-IKKα/β; Ser176/180), phospho-mTOR (p-mTOR; Ser2448), and phospho-S6 ribosomal protein (p-S6; Ser235/236). Membranes were probed for β-actin and CGI-58 to serve as loading controls; data from four representative animals are shown for each group.
FIG. 2. CGI-58 KD alters HFD-induced inflammation: Evidence of hepatic cytokine resistance. C57BL/6N mice were fed either a standard chow or HFD in conjunction with biweekly injections of either a nontargeting control ASO (□) or ASO targeting KD of CGI-58 (CGI-58 ASO; ■) for 10 weeks. A: Plasma levels of proinflammatory cytokines, including IL-6 and IL-12p40; monocyte chemoattractant protein-1 (MCP-1); macrophage inflammatory protein-2 (MIP-2); CXCL1 (KC); and regulated upon activation, normal T-cell expressed, and RANTES. Data represent the mean ± SEM from five mice per group, and values not sharing a common superscript letter differ significantly (P < 0.05). ND, levels below limit of detection. B and C: HFD-induced stress kinase activation. Representative immunoblots from liver (B) or epididymal adipose tissue (C) are shown for phospho-IκB kinase α/β (p-IKKα/β; Ser176/180), phospho-mTOR (p-mTOR; Ser2448), and phospho-S6 ribosomal protein (p-S6; Ser235/236). Membranes were probed for β-actin and CGI-58 to serve as loading controls; data from four representative animals are shown for each group.CC BY-NC-ND · PubMed Central
FIG. 3. CGI-58–generated signaling lipids are necessary for maximal TNFα signaling in the liver. A–C: Mice were maintained on a chow diet for 4 weeks in conjunction with biweekly injections (25 mg/kg) of either a nontargeting control ASO (□) or ASO targeting knockdown of CGI-58 (CGI-58 ASO; ■). Mice were fasted for 10 h before injection of saline or TNFα (10 ng) into the portal vein. Exactly 5 min later, the liver was excised and immediately snap-frozen in liquid nitrogen for signaling analyses. A: Hepatic levels of PA and phosphatidylglycerol (PG) were analyzed by mass spectrometry. B: Total hepatic LPAAT activity. Data in A and B represent the mean ± SEM from four mice per group, and values not sharing a common superscript letter differ significantly (P < 0.05). C: Protein extracts from the liver were analyzed for total IκB α (IκBα) and phospho-IκBα (p-IκBα; Ser32); data from four representative animals are shown for each group. D–F: Acute stress kinase activation in primary hepatocytes. Following 4 weeks of ASO treatment, hepatocytes were isolated from control and CGI-58 ASO-treated mice by collagenase perfusion. Freshly isolated hepatocytes were stimulated for 15 min (15’) or 1 h with 100 ng/mL TNFα (D), 10 ng/mL IL-1β (E), or 10 ng/mL IL-6 (F). Downstream signaling was analyzed by immunoblotting for p-JNK (Thr183/Tyr185), phospho-S6 ribosomal protein (p-S6; Ser235/236), and β-actin. Data in D–F represent responses of hepatocytes isolated from three individual mice per condition.
FIG. 3. CGI-58–generated signaling lipids are necessary for maximal TNFα signaling in the liver. A–C: Mice were maintained on a chow diet for 4 weeks in conjunction with biweekly injections (25 mg/kg) of either a nontargeting control ASO (□) or ASO targeting knockdown of CGI-58 (CGI-58 ASO; ■). Mice were fasted for 10 h before injection of saline or TNFα (10 ng) into the portal vein. Exactly 5 min later, the liver was excised and immediately snap-frozen in liquid nitrogen for signaling analyses. A: Hepatic levels of PA and phosphatidylglycerol (PG) were analyzed by mass spectrometry. B: Total hepatic LPAAT activity. Data in A and B represent the mean ± SEM from four mice per group, and values not sharing a common superscript letter differ significantly (P < 0.05). C: Protein extracts from the liver were analyzed for total IκB α (IκBα) and phospho-IκBα (p-IκBα; Ser32); data from four representative animals are shown for each group. D–F: Acute stress kinase activation in primary hepatocytes. Following 4 weeks of ASO treatment, hepatocytes were isolated from control and CGI-58 ASO-treated mice by collagenase perfusion. Freshly isolated hepatocytes were stimulated for 15 min (15’) or 1 h with 100 ng/mL TNFα (D), 10 ng/mL IL-1β (E), or 10 ng/mL IL-6 (F). Downstream signaling was analyzed by immunoblotting for p-JNK (Thr183/Tyr185), phospho-S6 ribosomal protein (p-S6; Ser235/236), and β-actin. Data in D–F represent responses of hepatocytes isolated from three individual mice per condition.CC BY-NC-ND · PubMed Central
FIG. 4. CGI-58 KD alters the systemic inflammatory and metabolic response to endotoxin. C57BL/6N mice were fed a standard chow diet in conjunction with biweekly injections of a nontargeting control ASO (□) or CGI-58 ASO (■) for 4 weeks. Thereafter, mice received a single intraperitoneal injection of either saline or LPS (5 μg/mouse) and were necropsied 6 h after injection. A: Plasma cytokine and acute-phase response protein levels were measured at 1 h (for TNFα only) and 6 h after injection (for IL-6 and IL-12p40 and for SAA and haptoglobin). ND, levels below limit of detection. B and C: qPCR analyses of hepatic (B) and epididymal adipose tissue (C) gene expression. SAP, serum amyloid P-component. WAT, white adipose tissue. D: Hepatic TAG levels. E: Plasma TAG levels at 6 h after injection. Data in A, D, and E represent the mean ± SEM (n = 6), and qPCR data in B and C represent the mean ± SEM (n = 5). Within each panel, values not sharing a common superscript letter differ significantly (P < 0.05). AU, arbitrary unit.
FIG. 4. CGI-58 KD alters the systemic inflammatory and metabolic response to endotoxin. C57BL/6N mice were fed a standard chow diet in conjunction with biweekly injections of a nontargeting control ASO (□) or CGI-58 ASO (■) for 4 weeks. Thereafter, mice received a single intraperitoneal injection of either saline or LPS (5 μg/mouse) and were necropsied 6 h after injection. A: Plasma cytokine and acute-phase response protein levels were measured at 1 h (for TNFα only) and 6 h after injection (for IL-6 and IL-12p40 and for SAA and haptoglobin). ND, levels below limit of detection. B and C: qPCR analyses of hepatic (B) and epididymal adipose tissue (C) gene expression. SAP, serum amyloid P-component. WAT, white adipose tissue. D: Hepatic TAG levels. E: Plasma TAG levels at 6 h after injection. Data in A, D, and E represent the mean ± SEM (n = 6), and qPCR data in B and C represent the mean ± SEM (n = 5). Within each panel, values not sharing a common superscript letter differ significantly (P < 0.05). AU, arbitrary unit.CC BY-NC-ND · PubMed Central
FIG. 5. Proposed model for CGI-58’s integrated role in inflammatory responses and insulin action in the liver. In response to inflammatory stimuli, such as an HFD or LPS, plasma levels of inflammatory cytokines, such TNFα, IL-1β, and IL-6, are increased. These inflammatory cytokines normally signal through their membrane-bound receptors (TNF-R, IL-6-R, and IL-1-R) to promote CGI-58–driven generation of signaling lipids either directly from LPAAT activity or indirectly by coactivating ATGL to generate lipid signals from TAG hydrolysis. CGI-58–generated PA, and likely other signaling lipids, can subsequently act as a critical second messenger to promote the activation of inflammatory stress kinases, such as IKK-β, S6K1, and mTOR. Collectively, these activated stress kinases (IKK-β, S6K1, and mTOR) can facilitate serine phosphorylation (pS) of critical serine residues (Ser307, Ser612, Ser632, and Ser1101) on IRS-1, thereby dampening hepatic insulin signaling. Knocking down CGI-58 diminishes this potent negative regulatory loop, thereby improving hepatic insulin action. IR, insulin receptor. TNF-R, TNF receptor.
FIG. 5. Proposed model for CGI-58’s integrated role in inflammatory responses and insulin action in the liver. In response to inflammatory stimuli, such as an HFD or LPS, plasma levels of inflammatory cytokines, such TNFα, IL-1β, and IL-6, are increased. These inflammatory cytokines normally signal through their membrane-bound receptors (TNF-R, IL-6-R, and IL-1-R) to promote CGI-58–driven generation of signaling lipids either directly from LPAAT activity or indirectly by coactivating ATGL to generate lipid signals from TAG hydrolysis. CGI-58–generated PA, and likely other signaling lipids, can subsequently act as a critical second messenger to promote the activation of inflammatory stress kinases, such as IKK-β, S6K1, and mTOR. Collectively, these activated stress kinases (IKK-β, S6K1, and mTOR) can facilitate serine phosphorylation (pS) of critical serine residues (Ser307, Ser612, Ser632, and Ser1101) on IRS-1, thereby dampening hepatic insulin signaling. Knocking down CGI-58 diminishes this potent negative regulatory loop, thereby improving hepatic insulin action. IR, insulin receptor. TNF-R, TNF receptor.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Lord, C. C., Betters, J. L., Ivanova, P. T., Milne, S. B., Myers, D. S., Madenspacher, J., Thomas, G., Chung, S., Liu, M., Davis, M. A., Lee, R. G., Crooke, R. M., Graham, M. J., Parks, J. S., Brasaemle, D. L., Fessler, M. B., Brown, H. A., & Brown, J. M.
Affiliations
  • Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
  • Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee
  • Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
  • Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California
  • Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
Venue
Diabetes
Publisher
American Diabetes Association
Published
2012-01-17
Volume
61
Issue
2
Pages
355-363
ISSN
  • 0012-1797
  • 1939-327X
DOI
10.2337/db11-0994
PMC
PMC3266405
Cited by
45
References
6
Language
en
Licence
creativecommons.org/licenses/by-nc-nd/3.0/ (vor, 3510 d)

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Lord, C. C., Betters, J. L., Ivanova, P. T., Milne, S. B., Myers, D. S., Madenspacher, J., Thomas, G., Chung, S., Liu, M., Davis, M. A., Lee, R. G., Crooke, R. M., Graham, M. J., Parks, J. S., Brasaemle, D. L., Fessler, M. B., Brown, H. A., & Brown, J. M. (2012). CGI-58/ABHD5-Derived Signaling Lipids Regulate Systemic Inflammation and Insulin Action. Diabetes. https://doi.org/10.2337/db11-0994