ApoA-I Milano stimulates lipolysis in adipose cells independently of cAMP/PKA activation

Lindahl, Maria; Petrlová, Jitka; Dalla-Riva, Jonathan; Wasserström, Sebastian; Rippe, Catarina; Domingo-Espín, Joan; Kotowska, Dorota; Krupinska, Ewa; Berggreen, Christine; Jones, Helena A.; Swärd, Karl; Lagerstedt, Jens O.; Göransson, Olga; Stenkula, Karin G.

doi:10.1194/jlr.m054767

Cited by 23 publications

(17 citation statements)

References 51 publications

(44 reference statements)

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“…Upstream mechanisms involved in GLP-1-mediated renal protection in diabetes are unclear but may involve activation of cAMP/PKA (52), which is a positive regulator of ABCA1 (18). Our results suggest that cAMP/PKA signaling contributes to the exendin-4-mediated restoration of ABCA1 expression under high glucose and high cholesterol conditions in HRGECs.…”

Section: Exendin-4 Improves Abca1-mediated Cholesterol Effluxmentioning

confidence: 78%

“…To further investigate the mechanism underlying the effect of exendin-4 on ABCA1-mediated cholesterol efflux in HRGECs, we analyzed GLP-1R-mediated signaling pathways, such as the cAMP/PKA pathway, which plays a role in cholesterol efflux (18,19). Intracellular cAMP activity was assessed by ELISA, and PKA activity was assessed by the Kemptide phosphorylation assay.…”

Section: Exendin-4 Attenuated Lipid Droplets Accumulation and Inflammmentioning

confidence: 99%

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Exendin-4 Ameliorates Lipotoxicity-induced Glomerular Endothelial Cell Injury by Improving ABC Transporter A1-mediated Cholesterol Efflux in Diabetic apoE Knockout Mice

Yin

Zhang

et al. 2016

Journal of Biological Chemistry

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Section: Exendin-4 Improves Abca1-mediated Cholesterol Effluxmentioning

confidence: 78%

Section: Exendin-4 Attenuated Lipid Droplets Accumulation and Inflammmentioning

confidence: 99%

Exendin-4 Ameliorates Lipotoxicity-induced Glomerular Endothelial Cell Injury by Improving ABC Transporter A1-mediated Cholesterol Efflux in Diabetic apoE Knockout Mice

Yin

Zhang

et al. 2016

Journal of Biological Chemistry

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“…However, the injected apoA-I has an effect on the circulating lipid profile, as shown by the lowered serum levels of FFA and TG already occurring within the 3-h time span, and alterations of specific lipids with potential regulatory roles in heart glucose uptake cannot be ruled out. For example, we and others (28)(29)(30) have previously shown that apoA-I-mediated cholesterol efflux and changes in the plasma membrane cholesterol content affect signaling pathways in adipocytes and pancreatic b-cells. Further studies focused on the detailed cellular regulatory mechanism will address this.…”

Section: Discussionmentioning

confidence: 99%

Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal

et al. 2016

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Apolipoprotein A-I (apoA-I) of HDL is central to the transport of cholesterol in circulation. ApoA-I also provides glucose control with described in vitro effects of apoA-I on β-cell insulin secretion and muscle glucose uptake. In addition, apoA-I injections in insulin-resistant diet-induced obese (DIO) mice lead to increased glucose-stimulated insulin secretion (GSIS) and peripheral tissue glucose uptake. However, the relative contribution of apoA-I as an enhancer of GSIS in vivo and as a direct stimulator of insulin-independent glucose uptake is not known. Here, DIO mice with instant and transient blockade of insulin secretion were used in glucose tolerance tests and in positron emission tomography analyses. Data demonstrate that apoA-I to an equal extent enhances GSIS and acts as peripheral tissue activator of insulin-independent glucose uptake and verify skeletal muscle as an apoA-I target tissue. Intriguingly, our analyses also identify the heart as an important target tissue for the apoA-I–stimulated glucose uptake, with potential implications in diabetic cardiomyopathy. Explorations of apoA-I as a novel antidiabetic drug should extend to treatments of diabetic cardiomyopathy and other cardiovascular diseases in patients with diabetes.

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“…Adipocytes were incubated with or without insulin as indicated in the figures. To stop incubations, cells were washed in KRBH without BSA, lysed and subjected to polyacrylamide gel electrophoresis and electrotransfer to nitrocellulose membranes as previously described (Lindahl et al 2015). Briefly, cell lysates (10 µg total protein) were heated and subjected to electrophoresis on pre-cast BioRad gradient gels and electrotransfer to nitrocellulose membrane.…”

Section: Western Blotmentioning

confidence: 99%

Intact glucose uptake despite deteriorating signaling in adipocytes with high-fat feeding

Hansson

Wasserström

Morén

et al. 2018

Journal of Molecular Endocrinology

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To capture immediate cellular changes during diet-induced expansion of adipocyte cell volume and number, we characterized mature adipocytes during a short-term high-fat diet (HFD) intervention. Male C57BL6/J mice were fed chow diet, and then switched to HFD for 2, 4, 6 or 14 days. Systemic glucose clearance was assessed by glucose tolerance test. Adipose tissue was dissected for RNA-seq and cell size distribution analysis using coulter counting. Insulin response in isolated adipocytes was monitored by glucose uptake assay and Western blotting, and confocal microscopy was used to assess autophagic activity. Switching to HFD was accompanied by an immediate adipocyte size expansion and onset of systemic insulin resistance already after two days, followed by recruitment of new adipocytes. Despite an initially increased non-stimulated and preserved insulin-stimulated glucose uptake, we observed a decreased phosphorylation of insulin receptor substrate-1 (IRS-1) and protein kinase B (PKB). After 14 days of HFD, both the insulin-stimulated phosphorylation of Akt substrate of 160 kDa (AS160) and glucose uptake was blunted. RNA-seq analysis of adipose tissue revealed transient changes in gene expression at day four, including highly significant upregulation of , previously demonstrated to be involved in autophagy. We confirmed increased autophagy, measured as an increased density of LC3-positive puncta and decreased p62 expression after 14 days of HFD. In conclusion, HFD rapidly induced systemic insulin resistance, whereas insulin-stimulated glucose uptake remained intact throughout 6 days of HFD feeding. We also identified autophagy as an early cellular process that potentially influences adipocyte function upon switching to HFD.

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ApoA-I Milano stimulates lipolysis in adipose cells independently of cAMP/PKA activation

Cited by 23 publications

References 51 publications

Exendin-4 Ameliorates Lipotoxicity-induced Glomerular Endothelial Cell Injury by Improving ABC Transporter A1-mediated Cholesterol Efflux in Diabetic apoE Knockout Mice

Exendin-4 Ameliorates Lipotoxicity-induced Glomerular Endothelial Cell Injury by Improving ABC Transporter A1-mediated Cholesterol Efflux in Diabetic apoE Knockout Mice

Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal

Intact glucose uptake despite deteriorating signaling in adipocytes with high-fat feeding

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