| 1. |
- Cansby, Emmelie, 1984, et al.
(författare)
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Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease.
- 2020
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Ingår i: JCI insight. - : American Society for Clinical Investigation. - 2379-3708. ; 5:24
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease (DKD) is the most common cause of severe renal disease worldwide and the single strongest predictor of mortality in diabetes patients. Kidney steatosis has emerged as a critical trigger in the pathogenesis of DKD; however, the molecular mechanism of renal lipotoxicity remains largely unknown. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase (STK)25 as a critical regulator of ectopic lipid storage in several metabolic organs prone to diabetic damage. Here, we demonstrate that overexpression of STK25 aggravates renal lipid accumulation and exacerbates structural and functional kidney injury in a mouse model of DKD. Reciprocally, inhibiting STK25 signaling in mice ameliorates diet-induced renal steatosis and alleviates the development of DKD-associated pathologies. Further, we find that STK25 silencing in human kidney cells protects against lipid deposition as well as oxidative and endoplasmic reticulum stress. Together, our results suggest that STK25 regulates a critical node governing susceptibility to renal lipotoxicity and that STK25 antagonism could mitigate DKD progression.
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| 2. |
- Gogg, Silvia, 1962, et al.
(författare)
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Breast volume in non-obese females is related to breast adipose cell hypertrophy, inflammation, and COX2 expression.
- 2024
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Ingår i: Journal of plastic surgery and hand surgery. - 2000-6764. ; 59, s. 83-88
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Tidskriftsartikel (refereegranskat)abstract
- Breast hypertrophy seems to be a risk factor for breast cancer and the amount and characteristics of breast adipose tissue may play important roles. The main aim of this study was to investigate associations between breast volume in normal weight women and hypertrophic adipose tissue and inflammation.Fifteen non-obese women undergoing breast reduction surgery were examined. Breast volume was measured with plastic cups and surgery was indicated if the breast was 800 ml or larger according to Swedish guidelines. We isolated adipose cells from the breasts and ambient subcutaneous tissue to measure cell size, cell inflammation and other known markers of risk of developing breast cancer including COX2 gene activation and MAPK, a cell proliferation regulator.Breast adipose cell size was characterized by cell hypertrophy and closely related to breast volume. The breast adipose cells were also characterized by being pro-inflammatory with increased IL-6, IL-8, IL-1β, CCL-2, TNF-a and an increased marker of cell senescence GLB1/β-galactosidase, commonly increased in hypertrophic adipose tissue. The prostaglandin synthetic marker COX2 was also increased in the hypertrophic cells and COX2 has previously been shown to be an important marker of risk of developing breast cancer. Interestingly, the phosphorylation of the proliferation marker MAPK was also increased in the hypertrophic adipose cells.Taken together, these findings show that increased breast volume in non-obese women is associated with adipose cell hypertrophy and dysfunction and characterized by increased inflammation and other markers of increased risk for developing breast cancer.Projektdatabasen FoU i VGR, project number: 249191 (https://www.researchweb.org/is/vgr/project/249191).
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| 3. |
- Gustafson, Birgit, 1951, et al.
(författare)
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Type 2 Diabetes, Independent of Obesity and Age, Is Characterized by Senescent and Dysfunctional Mature Human Adipose Cells
- 2022
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797. ; 71:11, s. 2372-2383
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Tidskriftsartikel (refereegranskat)abstract
- Obesity with dysfunctional adipose cells is the major cause of the current epidemic of type 2 diabetes (T2D). We examined senescence in human adipose tissue cells from age- and BMI-matched individuals who were lean, obese, and obese with T2D. In obese individuals and, more pronounced, thosewith T2D, we foundmature and fully differentiated adipose cells to exhibit increased senescence similar to what we previously have shown in the progenitor cells. The degree of adipose cell senescencewas positively correlated with whole-body insulin resistance and adipose cell size. Adipose cell protein analysis revealed dysfunctional cells in T2D with increased senescence markers reduced PPAR-gamma, GLUT4, and pS473AKT. Consistent with a recent study, we found the cell cycle regulator cyclin D1 to be increased in obese cells and further elevated in T2D cells, closely correlating with senescence markers, ambient donor glucose, and, more inconsistently, plasma insulin levels. Furthermore, fully differentiated adipose cells were susceptible to experimentally induced senescence and to conditioned medium increasing cyclin D1 and responsive to senolytic agents. Thus, fully mature human adipose cells from obese individuals, particularly those with T2D become senescent, and SASP secretion by senescent progenitor cells can play an important role in addition to donor hyperinsulinemia.
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| 4. |
- Nerstedt, Annika, 1960, et al.
(författare)
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Lipid droplet-associated kinase STK25 regulates peroxisomal activity and metabolic stress response in steatotic liver
- 2020
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Ingår i: Journal of Lipid Research. - 0022-2275. ; 61:2, s. 178-191
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide and have been recognized as one of the major unmet medical needs of the 21st century. Our recent translational studies in mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine kinase (STK)25 as a protein that coats intrahepatocellular lipid droplets (LDs) and critically regulates liver lipid homeostasis and progression of NAFLD/NASH. Here, we studied the mechanism-of-action of STK25 in steatotic liver by relative quantification of the hepatic LD-associated phosphoproteome from high-fat diet-fed Stk25 knockout mice compared with their wild-type littermates. We observed a total of 131 proteins and 60 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, ubiquitination-mediated proteolysis, and antioxidant defense were coordinately regulated in Stk25(-/-) versus wild-type livers. We confirmed attenuated peroxisomal biogenesis and protection against oxidative and ER stress in STK25-deficient human liver cells, demonstrating the hepatocyte-autonomous manner of STK25's action. In summary, our results suggest that regulation of peroxisomal function and metabolic stress response may be important molecular mechanisms by which STK25 controls the development and progression of NAFLD/NASH.
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| 5. |
- Nerstedt, Annika, 1960, et al.
(författare)
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The impact of cellular senescence in human adipose tissue
- 2023
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Ingår i: Journal of Cell Communication and Signaling. - 1873-9601. ; 17:3, s. 563-573
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Tidskriftsartikel (refereegranskat)abstract
- In the last decades the prevalence of obesity has increased dramatically, and the worldwide epidemic of obesity and related metabolic diseases has contributed to an increased interest for the adipose tissue (AT), the primary site for storage of lipids, as a metabolically dynamic and endocrine organ. Subcutaneous AT is the depot with the largest capacity to store excess energy and when its limit for storage is reached hypertrophic obesity, local inflammation, insulin resistance and ultimately type 2 diabetes (T2D) will develop. Hypertrophic AT is also associated with a dysfunctional adipogenesis, depending on the inability to recruit and differentiate new mature adipose cells. Lately, cellular senescence (CS), an aging mechanism defined as an irreversible growth arrest that occurs in response to various cellular stressors, such as telomere shortening, DNA damage and oxidative stress, has gained a lot of attention as a regulator of metabolic tissues and aging-associated conditions. The abundance of senescent cells increases not only with aging but also in hypertrophic obesity independent of age. Senescent AT is characterized by dysfunctional cells, increased inflammation, decreased insulin sensitivity and lipid storage. AT resident cells, such as progenitor cells (APC), non-proliferating mature cells and microvascular endothelial cells are affected with an increased senescence burden. Dysfunctional APC have both an impaired adipogenic and proliferative capacity. Interestingly, human mature adipose cells from obese hyperinsulinemic individuals have been shown to re-enter the cell cycle and senesce, which indicates an increased endoreplication. CS was also found to be more pronounced in mature cells from T2D individuals, compared to matched non-diabetic individuals, with decreased insulin sensitivity and adipogenic capacity.
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| 6. |
- Spinelli, Rosa, et al.
(författare)
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Increased cell senescence in human metabolic disorders
- 2023
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 133:12
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Forskningsöversikt (refereegranskat)abstract
- Cell senescence (CS) is at the nexus between aging and associated chronic disorders, and aging increases the burden of CS in all major metabolic tissues. However, CS is also increased in adult obesity, type 2 diabetes (T2D), and nonalcoholic fatty liver disease independent of aging. Senescent tissues are characterized by dysfunctional cells and increased inflammation, and both progenitor cells and mature, fully differentiated and nonproliferating cells are afflicted. Recent studies have shown that hyperinsulinemia and associated insulin resistance (IR) promote CS in both human adipose and liver cells. Similarly, increased CS promotes cellular IR, showing their interdependence. Furthermore, the increased adipose CS in T2D is independent of age, BMI, and degree of hyperinsulinemia, suggesting premature aging. These results suggest that senomorphic/senolytic therapy may become important for treating these common metabolic disorders.
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| 7. |
- Spinelli, R., et al.
(författare)
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ZMAT3 hypomethylation contributes to early senescence of preadipocytes from healthy first-degree relatives of type 2 diabetics
- 2022
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Ingår i: Aging Cell. - : Wiley. - 1474-9718 .- 1474-9726. ; 21:3
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Tidskriftsartikel (refereegranskat)abstract
- Senescence of adipose precursor cells (APC) impairs adipogenesis, contributes to the age-related subcutaneous adipose tissue (SAT) dysfunction, and increases risk of type 2 diabetes (T2D). First-degree relatives of T2D individuals (FDR) feature restricted adipogenesis, reflecting the detrimental effects of APC senescence earlier in life and rendering FDR more vulnerable to T2D. Epigenetics may contribute to these abnormalities but the underlying mechanisms remain unclear. In previous methylome comparison in APC from FDR and individuals with no diabetes familiarity (CTRL), ZMAT3 emerged as one of the top-ranked senescence-related genes featuring hypomethylation in FDR and associated with T2D risk. Here, we investigated whether and how DNA methylation changes at ZMAT3 promote early APC senescence. APC from FDR individuals revealed increases in multiple senescence markers compared to CTRL. Senescence in these cells was accompanied by ZMAT3 hypomethylation, which caused ZMAT3 upregulation. Demethylation at this gene in CTRL APC led to increased ZMAT3 expression and premature senescence, which were reverted by ZMAT3 siRNA. Furthermore, ZMAT3 overexpression in APC determined senescence and activation of the p53/p21 pathway, as observed in FDR APC. Adipogenesis was also inhibited in ZMAT3-overexpressing APC. In FDR APC, rescue of ZMAT3 methylation through senolytic exposure simultaneously downregulated ZMAT3 expression and improved adipogenesis. Interestingly, in human SAT, aging and T2D were associated with significantly increased expression of both ZMAT3 and the P53 senescence marker. Thus, DNA hypomethylation causes ZMAT3 upregulation in FDR APC accompanied by acquisition of the senescence phenotype and impaired adipogenesis, which may contribute to FDR predisposition for T2D.
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