| 1. |
- Andersson, Daniel P., et al.
(author)
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Relation among hypertriglyceridaemia, cardiometabolic disease, and hereditary factors : design and rationale of the Stockholm hyperTRIglyceridaemia REGister study
- 2024
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In: European Heart Journal Open. - : Oxford University Press. - 2752-4191. ; 4:2
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Journal article (peer-reviewed)abstract
- AimsHypertriglyceridaemia (hTG) is associated with atherosclerotic cardiovascular disease, pancreatitis, and non-alcoholic fatty liver disease (NAFLD) in large population-based studies. The understanding of the impact of hereditary hTG and cardiometabolic disease status on the development of hTG and its associated cardiometabolic outcomes is more limited. We aimed to establish a multigenerational cohort to enable studies of the relationship between hTG, cardiometabolic disease and hereditary factors.Methods and resultsThe population-based observational Stockholm hyperTRIglyceridaemia REGister (STRIREG) study includes 1 460 184 index individuals who have measured plasma triglycerides in the clinical routine in Region Stockholm, Sweden, between 1 January 2000 and 31 December 2021. The laboratory measurements also included basic haematology, blood lipid panel, liver function tests, and HbA1c. Using the Swedish Multi-Generation register, 2 147 635 parents and siblings to the indexes were identified to form the complete study cohort. Laboratory data from participants were combined with data from several national registers that provided information on the cause of death, medical diagnoses, dispensed medicines, and socioeconomic factors including country of birth, education level, and marital status.ConclusionThe multi-generational longitudinal STRIREG cohort provides a unique opportunity to investigate different aspects of hTG as well as heredity for other metabolic diseases. Important outcome measures include mortality, cardiovascular mortality, major cardiovascular events, development of incident diabetes, and NAFLD. The STRIREG study will provide a deeper understanding of the impact of hereditary factors and associated cardiometabolic complications.
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| 2. |
- Cansby, Emmelie, 1984, et al.
(author)
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Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease.
- 2020
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In: JCI insight. - : American Society for Clinical Investigation. - 2379-3708. ; 5:24
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Journal article (peer-reviewed)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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| 3. |
- Gonzalez-Granillo, Marcela, et al.
(author)
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Sex-specific lipid molecular signatures in obesity-associated metabolic dysfunctions revealed by lipidomic characterization in ob/ob mouse
- 2019
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In: Biology of Sex Differences. - : BMC. - 2042-6410. ; 10
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Journal article (peer-reviewed)abstract
- The response to overfeeding is sex dependent, and metabolic syndrome is more likely associated to obesity in men or postmenopausal women than in young fertile women. We hypothesized that obesity-induced metabolic syndrome is sex dependent due to a sex-specific regulation of the fatty acid (FA) synthesis pathways in liver and white adipose depots. We aimed to identify distinctive molecular signatures between sexes using a lipidomics approach to characterize lipid species in liver, perigonadal adipose tissue, and inguinal adipose tissue and correlate them to the physiopathological responses observed. Males had less total fat but lower subcutaneous on visceral fat ratio together with higher liver weight and higher liver and serum triglyceride (TG) levels. Males were insulin resistant compared to females. Fatty acid (FA) and TG profiles differed between sexes in both fat pads, with longer chain FAs and TGs in males compared to that in females. Remarkably, hepatic phospholipid composition was sex dependent with more abundant lipotoxic FAs in males than in females. This may contribute to the sexual dimorphism in response to obesity towards more metaflammation in males. Our work presents an exhaustive novel description of a sex-specific lipid signature in the pathophysiology of metabolic disorders associated with obesity in ob/ob mice. These data could settle the basis for future pharmacological treatment in obesity.
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| 4. |
- Littmann, Karin, et al.
(author)
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Plasma lipoprotein(a) measured in the routine clinical care is associated to atherosclerotic cardiovascular disease during a 14-year follow-up.
- 2021
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In: European Journal of Preventive Cardiology. - : Oxford University Press. - 2047-4873 .- 2047-4881. ; 28:18, s. 2038-2047
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Journal article (peer-reviewed)abstract
- AIMS: To investigate plasma lipoprotein(a) [Lp(a)] levels measured in routine clinical care and their association with mortality and cardiovascular disease.METHODS AND RESULTS: This retrospective registry-based observational cohort study includes all individuals with plasma Lp(a) results measured at the Karolinska University Laboratory 2003-17. Outcome data were captured in national outcome registries. Levels of Lp(a) expressed in mass or molar units were examined separately. In adjusted Cox regression models, association between deciles of plasma Lp(a) concentrations, mortality, and cardiovascular outcomes were assessed. A total of 23 398 individuals [52% females, mean (standard deviation) age 55.5 (17.2) years, median Lp(a) levels 17 mg/dL or 19.5 nmol/L] were included. Individuals with an Lp(a) level >90th decile (>90 mg/dL or >180 nmol/L) had hazard ratios (95% confidence interval) of 1.25 (1.05-1.50) for major adverse cardiovascular events (P = 0.013), 1.37 (1.14-1.64) for atherosclerotic cardiovascular disease (P = 0.001), and 1.62 (1.28-2.05) for coronary artery disease (P ≤ 0.001), compared to individuals with Lp(a) ≤50th decile. No association between Lp(a) and mortality, peripheral artery disease, or ischaemic stroke was observed.CONCLUSION: High Lp(a) levels are associated with adverse cardiovascular disease outcomes also in individuals with Lp(a) measured in routine clinical care. This supports the 2019 ESC/EAS recommendation to measure Lp(a) at least once during lifetime to assess cardiovascular risk and implies the need for intensive preventive therapy in patients with elevated Lp(a).
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| 5. |
- Nyrén, Rakel, 1986-
(author)
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Localization of lipoprotein lipase in mouse pancreas, kidney and placenta : impact of metabolic disturbances on cellular distribution and activity regulation
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Lipoprotein lipase (LPL) is the key enzyme for metabolism of triglycerides in plasma lipoproteins. In recent years many new facts about the enzyme and its regulation have been uncovered. The endothelial membrane protein GPIHBP1 translocates LPL through endothelial cells and holds the enzyme in place at the luminal side of the capillary endothelium. Some of the angiopoietin-like proteins (ANGPTLs) bind to LPL and are responsible for tissue-specific regulation of the enzyme’s catalytic activity. Most studies in the past have focused on LPL in adipose and muscle tissues. LPL is also present in several other tissues, but the localization and function of LPL at these sites have not been fully elucidated.One aim of the present thesis was to develop a protocol for immunolocalization of LPL in mouse tissues. In pancreas, the enzyme was localized to capillaries of the exocrine tissue, together with GPIHBP1, but also inside α- and β-cells. LPL in β-cells was absent in leptin-deficient ob/ob mice, but appeared after treatment with leptin. In kidney, LPL was mostly present within the proximal tubular cells of the nephron. In fed animals, LPL was also seen in intertubular vessels together with GPIHBP1. A LPL knock-out mouse model, MCKL0, was used to validate the specificity of our immuno-protocol. Kidneys from these mice showed no or very little staining for LPL. In mouse placenta, LPL was mostly found in capillaries of the labyrinth zone, where the exchange between fetal and maternal blood occurs.A second aim was to gain better understanding for when, how and why LPL activity is regulated in mouse kidneys, and how obesity induced by high-fat diet (HFD) affects the LPL system. LPL activity in kidneys was regulated by ANGPTL4 in a similar manner as LPL in white adipose tissue, but in contrast to adipose tissue, the kidney LPL did not contribute to the uptake of fatty acids from chylomicron triglycerides. We found that obesity and insulin resistance, induced by long-term feeding of HFD, abolished the nutritional regulation of LPL activity in kidneys of male, but not of female, mice. To directly study the uptake of energy substrates in mouse kidneys, we developed a protocol for measurement of radiolabeled substrates in kidneys using PET/CT with the tracers [18F]FDG (a glucose analogue) and [18F]FTHA (a fatty acid analogue) injected to blood. There was an increase in uptake of both tracers in fasted male mice that had been on long-term HFD, compared to controls, as revealed by scanning of perfused organs, ex vivo, 3 hours after the injections.A third aim was to study LPL and the function of ANGPTL4 in pregnant mice and placentas. ANGPTL4 is known to increase in human plasma throughout pregnancy. As ANGPTL4 levels rise, triglyceride levels increase as well. We used mice that either lacked (Angptl4-/-) or overexpressed Angptl4 (Angptl4-tg+/-), and compared them to wild-type mice. Plasma triglycerides and VLDL levels increased during pregnancy both in wild-type and in Angptl4-/- mice. The lipid profile in Angptl4-tg+/- was high already before conception, and did not change. LPL activity in placenta was, however, similar in all genotypes. The increase in ANGPTL4 in maternal blood during pregnancy might originate from placenta, but Angptl4 expression was also increased in maternal liver and subcutaneous white adipose tissue. The pups from Angptl4-tg+/- had reduced birthweight compared to pups from wild-type and Angptl4-/- mice.In conclusion, the present thesis provides information on the localization and possible functions of LPL and some of its regulator proteins in mouse pancreas, kidney and placenta. New data on the regulation of LPL activity in mouse kidney, and the effects of HFD and obesity, is presented, as well as insights into the potential role of ANGPTL4 for control of plasma triglyceride levels and fetal growth during mouse pregnancy.
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| 6. |
- Parini, Paolo
(author)
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Hormonal regulation of hepatic cholesterol and lipoprotein metabolism : effects of estrogen and growth hormone
- 1999
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Doctoral thesis (other academic/artistic)abstract
- Coronary heart disease is the result of the progression of atherosclerotic lesions, and represents the major cause of death in western countries. Age, male sex, plasma cholesterol, hypertension and smoking are major risk factors for atherosclerosis. Of these, an increased level of plasma cholesterol within low density lipoproteins is of particular importance. It is therefore important to understand how plasma cholesterol is regulated. This study aimed to increase our understanding of the role of growth hormone and estrogen, and their interplay, in the regulation of hepatic cholesterol and lipoprotein metabolism by studying the effects of these hormones both in vitro and in vivo. The following conclusions could be drawn: * GH specifically induces the low-density lipoprotein receptor (LDLR) in vitro, both at the protein and the mRNA level. This induction is mediated by GH receptors, and is independent of insulin-like growth factor-I release. * Hypophysectomy reduces the activity of important structures regulating hepatic cholesterol metabolism (cholesterol 7[alpha]-hydroxylase, hydroxy-methylglutaryl-coenzyme A reductase, and LDLR), and also decreases the fecal excretion of bile acids. * GH stimulates the cholesterol 7[alpha]-hydroxylase activity and bile acid synthesis in rats, and is important to maintain a normal plasma lipoprotein pattern. * The age-dependent hyperlipidemic lipoprotein profile can be reversed by GH infusion. * The effects of estrogen on lipid metabolism are biphasic in female rats. A reduction in plasma total, LDL and HDL cholesterol, together with an enhanced hepatic LDLR expression, occurs at supraphysiological doses. Estrogen at low doses stimulates cholesterol 7[alpha]-hydroxylase and hydroxy-methylglutaryl-coenzyme A reductase activities. * The stimulation of hepatic LDLR by high-dose estrogen involves estrogen receptors, since concomitant treatment with antiestrogens abolished the LDLR stimulation, both at the protein and at the mRNA level. * Continuous infusion, but not pulse injections, of GH increases the hepatic estrogen receptor expression in male rats. * The feminization of the plasma lipoprotein pattern by continuous GH infusion involves estrogen receptors since the treatment with antiestrogen completely blocked the effects of GH infusion on HDL. Our results indicate that, also under physiological conditions, growth hormone and estrogen are important factors in the regulation of hepatic cholesterol and lipoprotein metabolism in the rat.
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| 7. |
- 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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| 8. |
- 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. - : 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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| 9. |
- Pettersson, Hanna, 1968-
(author)
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Steroid-Metabolizing Cytochrome P450 (CYP) Enzymes in the Maintenance of Cholesterol and Sex Hormone Levels
- 2009
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Doctoral thesis (other academic/artistic)abstract
- The enzymes CYP27A1 and CYP7B1 are widely expressed in various human tissues and perform catalytic reactions in cholesterol homeostasis and endocrine signaling. We have investigated the metabolism of a synthetic oxysterol. In this study, we show that CYP27A1 is the enzyme responsible for a 28-hydroxylation of this oxysterol and that the rate of CYP27A1-mediated metabolism is relatively slow. This may give an explanation for the prolonged inhibitory effects on cholesterol biosynthesis that have been shown for this oxysterol. The current study contributes to the knowledge of synthetically produced oxysterols and their potential use as cholesterol lowering drugs. In two studies we investigated CYP7B1-mediated metabolism of different sex hormones. Our data indicate that CYP7B1 may carry out a previously unknown catalytic reaction involving an androgen. Taken together the data suggest that varying steroid concentrations in cells and tissues may be important for CYP7B1-dependent metabolism of sex hormones and sex hormone precursors. CYP7B1-mediated hydroxylation of sex hormones may influence the cellular levels of these steroids and may be a potential pathway for elimination of the steroids from the cell. Some known CYP7B1 substrates are agonists for ERα and ERβ but the reported role(s) of CYP7B1 for ER action are not fully understood. In the last study we investigated the role(s) of CYP7B1-mediated metabolism for ER-mediated action. Our data indicate that CYP7B1-mediated conversion of steroids that affect ER-mediated response into their 7α-hydroxymetabolites will result in loss of action. This indicates that CYP7B1 may have an important role for regulation of ER-mediated processes in the body. In summary, results from this thesis contribute to the knowledge on the metabolism of synthetic oxysterols of potential use as cholesterol lowering drugs and the role(s) of CYP7B1-mediated metabolism for processes related to the functions of sex hormones.
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| 10. |
- Ramos, Pedro, et al.
(author)
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It takes two to dance the VBHC tango : A multiple case study of the adoption of value-based strategies in Sweden and Brazil
- 2021
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In: Social Science and Medicine. - Oxford : Elsevier. - 0277-9536 .- 1873-5347. ; 282
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Journal article (peer-reviewed)abstract
- Although Value-Based Health Care (VBHC) is widely debated and cited, there are few empirical studies focused on how its concepts are understood and applied in real-world contexts. This comparative case study of two prominent adopters in Brazil and Sweden, situated at either end of the spectrum in terms of contextual prerequisites, provides insights into the complex interactions involved in the adoption of value-based strategies. We found that the adoption of VBHC emphasized either health outcomes or costs – not both as suggested by the value equation. This may be linked to broader health system and societal contexts. Implementation can generate tensions with traditional business models, suggesting that providers should first analyze how these strategies align with their internal context. Adoption by a single provider organization is challenging, if not impossible. An effective VBHC transformation seems to require a systematic and systemic approach where all stakeholders need to clearly define the purpose and the scope of the transformation, and together steer their actions and decisions accordingly. © 2021 The Authors
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