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- Fernandez, C., et al.
(författare)
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Plasma levels of the proprotein convertase furin and incidence of diabetes and mortality
- 2018
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820. ; 284:4, s. 377-387
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Tidskriftsartikel (refereegranskat)abstract
- Background: Diabetes mellitus is linked to premature mortality of virtually all causes. Furin is a proprotein convertase broadly involved in the maintenance of cellular homeostasis; however, little is known about its role in the development of diabetes mellitus and risk of premature mortality. Objectives: To test if fasting plasma concentration of furin is associated with the development of diabetes mellitus and mortality. Methods: Overnight fasted plasma furin levels were measured at baseline examination in 4678 individuals from the population-based prospective Malmö Diet and Cancer Study. We studied the relation of plasma furin levels with metabolic and hemodynamic traits. We used multivariable Cox proportional hazards models to investigate the association between baseline plasma furin levels and incidence of diabetes mellitus and mortality during 21.3–21.7 years follow-up. Results: An association was observed between quartiles of furin concentration at baseline and body mass index, blood pressure and plasma concentration of glucose, insulin, LDL and HDL cholesterol (|0.11| ≤ β ≤ |0.31|, P < 0.001). Plasma furin (hazard ratio [HR] per one standard deviation increment of furin) was predictive of future diabetes mellitus (727 events; HR = 1.24, CI = 1.14–1.36, P < 0.001) after adjustment for age, sex, body mass index, systolic and diastolic blood pressure, use of antihypertensive treatment, alcohol intake and fasting plasma level of glucose, insulin and lipoproteins cholesterol. Furin was also independently related to the risk of all-cause mortality (1229 events; HR = 1.12, CI = 1.05–1.19, P = 0.001) after full multivariable adjustment. Conclusion: Individuals with high plasma furin concentration have a pronounced dysmetabolic phenotype and elevated risk of diabetes mellitus and premature mortality.
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| 2. |
- Salonurmi, Tuire, et al.
(författare)
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4β-Hydroxycholesterol Signals From the Liver to Regulate Peripheral Cholesterol Transporters.
- 2020
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Activation of pregnane X receptor (PXR) elevates circulating 4β-hydroxycholesterol (4βHC), an agonist of liver X receptor (LXR). PXR may also regulate 25-hydroxycholesterol and 27-hydroxycholesterol. Our aim was to elucidate the roles of PXR and oxysterols in the regulation of cholesterol transporters. We measured oxysterols in serum of volunteers dosed with PXR agonist rifampicin 600 mg/day versus placebo for a week and analyzed the expression of cholesterol transporters in mononuclear cells. The effect of 4βHC on the transport of cholesterol and the expression of cholesterol transporters was studied in human primary monocyte-derived macrophages and foam cells in vitro. The expression of cholesterol transporters was measured also in rat tissues after dosing with a PXR agonist. The levels of 4βHC were elevated, while 25-hydroxycholesterol and 27-hydroxycholesterol remained unchanged in volunteers dosed with rifampicin. The expression of ATP binding cassette transporter A1 (ABCA1) was induced in human mononuclear cells in vivo. The influx of cholesterol was repressed by 4βHC, as was the expression of influx transporter lectin-like oxidized LDL receptor-1 in vitro. The cholesterol efflux and the expression of efflux transporters ABCA1 and ABCG1 were induced. The expression of inducible degrader of the LDL receptor was induced. In rats, PXR agonist increased circulating 4βHC and expression of LXR targets in peripheral tissues, especially ABCA1 and ABCG1 in heart. In conclusion, PXR activation-elevated 4βHC is a signaling molecule that represses cholesterol influx and induces efflux. The PXR-4βHC-LXR pathway could link the hepatic xenobiotic exposure and the regulation of cholesterol transport in peripheral tissues.
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