| 11. |
- Landfors, Fredrik, et al.
(author)
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Genetic mimicry analysis reveals the specific lipases targeted by the ANGPTL3-ANGPTL8 complex and ANGPTL4
- 2023
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In: Journal of Lipid Research. - : Elsevier. - 0022-2275 .- 1539-7262. ; 64:1
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Journal article (peer-reviewed)abstract
- Angiopoietin-like proteins, ANGPTL3, ANGPTL4, and ANGPTL8, are involved in regulating plasma lipids. In vitro and animal-based studies point to LPL and endothelial lipase (EL, LIPG) as key targets of ANGPTLs. To examine the ANGPTL mechanisms for plasma lipid modulation in humans, we pursued a genetic mimicry analysis of enhancing or suppressing variants in the LPL, LIPG, lipase C hepatic type (LIPC), ANGPTL3, ANGPTL4, and ANGPTL8 genes using data on 248 metabolic parameters derived from over 110,000 nonfasted individuals in the UK Biobank and validated in over 13,000 overnight fasted individuals from 11 other European populations. ANGPTL4 suppression was highly concordant with LPL enhancement but not HL or EL, suggesting ANGPTL4 impacts plasma metabolic parameters exclusively via LPL. The LPL-independent effects of ANGPTL3 suppression on plasma metabolic parameters showed a striking inverse resemblance with EL suppression, suggesting ANGPTL3 not only targets LPL but also targets EL. Investigation of the impact of the ANGPTL3-ANGPTL8 complex on plasma metabolite traits via the ANGPTL8 R59W substitution as an instrumental variable showed a much higher concordance between R59W and EL activity than between R59W and LPL activity, suggesting the R59W substitution more strongly affects EL inhibition than LPL inhibition. Meanwhile, when using a rare and deleterious protein-truncating ANGPTL8 variant as an instrumental variable, the ANGPTL3-ANGPTL8 complex was very LPL specific. In conclusion, our analysis provides strong human genetic evidence that the ANGPTL3-ANGPTL8 complex regulates plasma metabolic parameters, which is achieved by impacting LPL and EL. By contrast, ANGPTL4 influences plasma metabolic parameters exclusively via LPL.
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| 12. |
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| 13. |
- Nilsson, Oktawia, et al.
(author)
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Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux
- 2021
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In: Journal of Lipid Research. - : Elsevier. - 0022-2275 .- 1539-7262. ; 62
-
Journal article (peer-reviewed)abstract
- Apolipoprotein A-I (ApoA-I) of high density lipoproteins (HDLs) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in ApoA-I of HDLs are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/HDL cholesterol. To explain this paradox, we show that the HDL particle profiles of patients carrying either L75P or L174S ApoA-I amyloidogenic variants show a higher relative abundance of the 8.4-nm versus 9.6-nm particles and that serum from patients, as well as reconstituted 8.4- and 9.6-nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4-nm rHDL have altered secondary structure composition and display a more flexible binding to lipids than their native counterpart. The reduced HDL cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles, and better cholesterol efflux due to altered, region-specific protein structure dynamics.
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| 14. |
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| 15. |
- Pedrelli, Matteo, et al.
(author)
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Vasculoprotective Properties of Plasma Lipoproteins from Brown Bears (Ursus arctos)
- 2021
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In: Journal of Lipid Research. - : American Society for Biochemistry and Molecular Biology. - 0022-2275 .- 1539-7262. ; 62
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Journal article (peer-reviewed)abstract
- Plasma cholesterol and triglyceride levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early-stage atherosclerosis development when adult. To explore this apparent paradox, we analysed plasma lipoproteins from the same ten bears in winter (hibernation) and in summer using size exclusion chromatography, ultracentrifugation and electrophoresis. LDL cholesterol binding to arterial proteoglycans, and plasma cholesterol efflux capacity were also evaluated. The data collected and analysed from bears were also compared with those from healthy humans. In bears the cholesterol esters, unesterified cholesterol, triglyceride and phospholipid content of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans, but did not change seasonally in bears. Bear LDL was larger, richer in triglycerides, showed pre-beta electrophoretic mobility and had 5-10 times lower binding to arterial proteoglycans than human LDL. Finally, plasma cholesterol efflux capacity was higher in bears than in humans, especially the HDL fraction when mediated by ABCA1. These results suggest that in brown bears the absence of early atherogenesis is likely associated with a lower affinity of LDL cholesterol for arterial proteoglycans and an elevated cholesterol efflux capacity of bear plasma.
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| 16. |
- Pedrelli, Matteo, et al.
(author)
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Vasculoprotective properties of plasma lipoproteins from brown bears (Ursus arctos)
- 2021
-
In: Journal of Lipid Research. - : Elsevier. - 0022-2275 .- 1539-7262. ; 62
-
Journal article (peer-reviewed)abstract
- Plasma cholesterol and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early stage atherosclerosis development when adult. To explore this apparent paradox, we analyzed plasma lipoproteins from the same 10 bears in winter (hibernation) and summer using size exclusion chromatography, ultracentrifugation, and electrophoresis. LDL binding to arterial proteoglycans (PGs) and plasma cholesterol efflux capacity (CEC) were also evaluated. The data collected and analyzed from bears were also compared with those from healthy humans. In bears, the cholesterol ester, unesterified cholesterol, TG, and phospholipid contents of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans but did not change seasonally in bears. Bear LDL was larger, richer in TGs, showed prebeta electrophoretic mobility, and had 5-10 times lower binding to arterial PGs than human LDL. Finally, plasma CEC was higher in bears than in humans, especially the HDL fraction when mediated by ABCA1. These results suggest that in brown bears the absence of early atherogenesis is likely associated with a lower affinity of LDL for arterial PGs and an elevated CEC of bear plasma.
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| 17. |
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| 18. |
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| 19. |
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| 20. |
- Skoug, Cecilia, et al.
(author)
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Hormone-sensitive lipase is localized at synapses and is necessary for normal memory functioning in mice
- 2022
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In: Journal of Lipid Research. - : Elsevier BV. - 1539-7262 .- 0022-2275. ; 63:5
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Journal article (peer-reviewed)abstract
- Hormone-sensitive lipase (HSL) is mainly present in adipose tissue where it hydrolyses diacylglycerol. Although expression of HSL has also been reported in the brain, its presence in different cellular compartments is uncertain, and its role in regulating brain lipid metabolism remains hitherto unexplored. We hypothesized HSL might play a role in regulating the availability of bioactive lipids necessary for neuronal function, and therefore investigated whether dampening HSL activity could lead to brain dysfunction. In mice, we found HSL protein and enzymatic activity throughout the brain, both localized within neurons and enriched in synapses. HSL-null mice were then analyzed using a battery of behavioral tests. Relative to wild-type littermates, HSL-null mice showed impaired short- and long-term memory, yet preserved exploratory behaviurs. Molecular analysis of the cortex and hippocampus showed increased expression of genes involved in glucose utilization in the hippocampus, but not cortex, of HSL-null mice compared to controls. Furthermore, lipidomics analyses indicated an impact of HSL deletion on the profile of bioactive lipids, including a decrease in endocannabinoids and eicosanoids that are known to modulate neuronal activity, cerebral blood flow, and inflammation processes. Accordingly, mild increases in the expression of pro-inflammatory cytokines in HSL mice compared to littermates were suggestive of low-grade inflammation. We conclude that HSL has a homeostatic role in maintaining pools of lipids required for normal brain function. It remains to be tested, however, whether the recruitment of HSL for the synthesis of these lipids occurs during increased neuronal activity, or whether HSL participates in neuroinflammatory responses.
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