| 1. |
- Andersson, R., et al.
(författare)
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Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments
- 2017
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1573-8744 .- 1567-567X. ; 44:3, s. 203-222
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Tidskriftsartikel (refereegranskat)abstract
- Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc-FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague-Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 , respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be 2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures.
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| 2. |
- Bonnet, Laurianne, et al.
(författare)
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Cellular senescence in hepatocytes contributes to metabolic disturbances in NASH
- 2022
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Cellular senescence is a state of irreversible cell cycle arrest and has been shown to play a key role in many diseases, including metabolic diseases. To investigate the potential contribution of hepatocyte cellular senescence to the metabolic derangements associated with non-alcoholic steatohepatitis (NASH), we treated human hepatocyte cell lines HepG2 and IHH with the senescence-inducing drugs nutlin-3a, doxorubicin and etoposide. The senescence-associated markers p16, p21, p53 and beta galactosidase were induced upon drug treatment, and this was associated with increased lipid storage, increased expression of lipid transporters and the development of hepatic steatosis. Drug-induced senescence also led to increased glycogen content, and increased VLDL secretion from hepatocytes. Senescence was also associated with an increase in glucose and fatty acid oxidation capacity, while de novo lipogenesis was decreased. Surprisingly, cellular senescence caused an overall increase in insulin signaling in hepatocytes, with increased insulin-stimulated phosphorylation of IR, Akt, and MAPK. Together, these data indicate that hepatic senescence plays a causal role in the development of NASH pathogenesis, by modulating glucose and lipid metabolism, favoring steatosis. Our findings contribute to a better understanding of the mechanisms linking cellular senescence and fatty liver disease and support the development of new therapies targeting senescent cells for the treatment of NASH.
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| 3. |
- Dutta, Tanmoy, 1998, et al.
(författare)
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Mitochondrial amidoxime-reducing component 1 p.Ala165Thr increases protein degradation mediated by the proteasome.
- 2024
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Ingår i: Liver international. - 1478-3223. ; 44:5, s. 1219-1232
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern with no effective and specific drug treatment available. The rs2642438 minor allele in mitochondrial amidoxime-reducing component 1 (MARC1) results in an aminoacidic substitution (p.Ala165Thr) and associates with protection against MASLD. However, the mechanisms behind this protective effect are unknown. In this study, we examined the consequences of this aminoacidic substitution on protein stability and subcellular localization.We overexpressed the human MARC1 A165 (wild-type) or 165T (mutant) invivo in mice and invitro in human hepatoma cells (HepG2 and HuH-7), generated several mutants at position 165 by insitu mutagenesis and then examined protein levels. We also generated HepG2 cells stably overexpressing MARC1 A165 or 165T to test the effect of this substitution on MARC1 subcellular localization.MARC1 165T overexpression resulted in lower protein levels than A165 both invivo and invitro. Similarly, any mutant at position 165 showed lower protein levels compared to the wild-type protein. We showed that the 165T mutant protein is polyubiquitinated and its degradation is accelerated through lysine-48 ubiquitin-mediated proteasomal degradation. We also showed that the 165T substitution does not affect the MARC1 subcellular localization.This study shows that alanine at position 165 in MARC1 is crucial for protein stability, and the threonine substitution at this position leads to a hypomorphic protein variant due to lower protein levels. Our result supports the notion that lowering hepatic MARC1 protein level may be a successful therapeutic strategy for treating MASLD.
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| 4. |
- Kroon, Tobias, et al.
(författare)
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Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats
- 2022
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Ingår i: Science translational medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 14:668
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Tidskriftsartikel (refereegranskat)abstract
- Circadian rhythms play a critical role in regulating metabolism, including daily cycles of feeding/fasting. Glucokinase (GCK) is central for whole-body glucose homeostasis and oscillates according to a circadian clock. GCK activators (GKAs) effectively reduce hyperglycemia, but their use is also associated with hypoglycemia, hyperlipidemia, and hepatic steatosis. Given the circadian rhythmicity and natural postprandial activation of GCK, we hypothesized that GKA treatment would benefit from being timed specifically during feeding periods. Acute treatment of obese Zucker rats with the GKA AZD1656 robustly increased flux into all major metabolic pathways of glucose disposal, enhancing glucose elimination. Four weeks of continuous AZD1656 treatment of obese Zucker rats improved glycemic control; however, hepatic steatosis and inflammation manifested. In contrast, timing AZD1656 to feeding periods robustly reduced hepatic steatosis and inflammation in addition to improving glycemia, whereas treatment timed to fasting periods caused overall detrimental metabolic effects. Mechanistically, timing AZD1656 to feeding periods diverted newly synthesized lipid toward direct VLDL secretion rather than intrahepatic storage. In line with increased hepatic insulin signaling, timing AZD1656 to feeding resulted in robust activation of AKT, mTOR, and SREBP-1C after glucose loading, pathways known to regulate VLDL secretion and hepatic de novo lipogenesis. In conclusion, intermittent AZD1656 treatment timed to feeding periods promotes glucose disposal when needed the most, restores metabolic flexibility and hepatic insulin sensitivity, and thereby avoids hepatic steatosis. Thus, chronotherapeutic approaches may benefit the development of GKAs and other drugs acting on metabolic targets.
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| 5. |
- Kroon, Tobias, et al.
(författare)
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Dosing profile profoundly influences nicotinic acid's ability to improve metabolic Control in rats
- 2015
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Ingår i: Journal of Lipid Research. - 0022-2275 .- 1539-7262. ; 56, s. 1679-1690
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Tidskriftsartikel (refereegranskat)abstract
- Acute nicotinic acid (NiAc) administration results in rapid reduction of plasma FFA concentrations. However, sustained NiAc exposure is associated with tolerance development resulting in return of FFA to pretreatment levels. The aim of this study was to determine whether a 12 h rectangular exposure profile (intermittent dose group) could avoid tolerance development and thereby reverse insulin resistance induced by lipid overload. FFA lowering was assessed in male Sprague Dawley (lean) and obese Zucker rats (obese) in response to a 5 h NiAc infusion, in either NiAc-naive animals or after 5 days of continuous (24 h/day) or intermittent (12 h/day) NiAc dosing (via implantable, programmable minipump). We found that intermittent dosing over 5 days preserved NiAc-induced FFA lowering, comparable to dosing in NiAc-naive animals. By contrast, following 5 days continuous administration, NiAc-induced FFA lowering was lost. The effect of intermittent NiAc infusion on insulin sensitivity was assessed in obese Zucker rats using hyperinsulinemic-isoglycemic clamps. The acute effect of NiAc to elevate glucose infusion rate (vs. saline control) was indeed preserved with intermittent dosing, while being lost upon continuous infusion. In conclusion, an intermittent but not continuous NiAc dosing strategy succeeded in retaining NiAc's ability to lower FFA and improve insulin sensitivity in obese Zucker rats.Kroon, T., A. Kjellstedt, P. Thalen, J. Gabrielsson, and N. D. Oakes.
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| 6. |
- Kroon, Tobias, et al.
(författare)
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Feedback modeling of non-esterified fatty acids in obese Zucker rats after nicotinic acid infusions
- 2013
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 40, s. 623-638
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Tidskriftsartikel (refereegranskat)abstract
- This study investigates the impact of disease on nicotinic acid (NiAc)-induced changes in plasma concentrations of non-esterified fatty acids (NEFA). NiAc was given by constant intravenous infusion to normal Sprague-Dawley and obese Zucker rats, and arterial blood samples were taken for analysis of NiAc, NEFA, insulin and glucose plasma concentrations. The intravenous route was intentionally selected to avoid confounding processes, such as absorption, following extravascular administration. Data were analyzed using nonlinear mixed effects modeling (NONMEM, version VI). The disposition of NiAc in the normal rats was described by a two-compartment model with endogenous synthesis of NiAc and two parallel capacity-limited elimination processes. In the obese rats disposition was described by a one-compartment model with endogenous synthesis of NiAc and one capacity-limited elimination process. The plasma concentration of NiAc drove NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M (1) ) inhibited the formation of R and the last compartment (M (N) ) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. Differences in the pharmacodynamic response of the two strains included, in the obese animals, an increased NEFA baseline, diminished rebound and post-rebound oscillation, and a more pronounced slowly developing tolerance during the period of constant drug exposure. The feedback model captured the NiAc-induced changes in NEFA response in both the normal and obese rats. Differences in the parameter estimates between the obese and normal rats included, in the former group, increases in R (0) , k (in) and p by 44, 41 and 78 %, respectively, and decreases in k (out) and gamma by 64 and 84 %, respectively. The estimates of k (tol) and IC (50) were similar in both groups. The NiAc-NEFA concentration-response relationship at equilibrium was substantially different in the two groups, being shifted upwards and to the right, and being shallower in the obese rats. The extent of such shifts is important, as they demonstrate the impact of disease at equilibrium and, if ignored, will lead to erroneous dose predictions and, in consequence, poorly designed studies. The proposed models are primarily aimed at screening and selecting candidates with the highest potential of becoming a viable drug in man.
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| 7. |
- Kroon, Tobias, et al.
(författare)
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Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats
- 2017
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Ingår i: Journal of Lipid Research. - 0022-2275 .- 1539-7262. ; 58, s. 31-41
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Tidskriftsartikel (refereegranskat)abstract
- Nicotinic acid (NiAc) is a potent inhibitor of lipolysis, acutely reducing plasma free fatty acid (FFA) concentrations. However, a major FFA rebound is seen during rapid NiAc washout, and sustained exposure is associated with tolerance development, with FFAs returning to pretreatment levels. Our aim was to find a rational NiAc dosing regimen that preserves FFA lowering, sufficient to reverse nonadipose tissue lipid accumulation and improve metabolic control, in obese Zucker rats. We compared feeding-period versus fasting-period NiAc dosing for 5 days: 12 h subcutaneous infusion (programmable, implantable mini-pumps) terminated by gradual withdrawal. It was found that NiAc timed to feeding decreased triglycerides in liver (-47%; P < 0.01) and heart (-38%; P < 0.05) and reduced plasma fructosamine versus vehicle. During oral glucose tolerance test, plasma FFA levels were reduced with amelioration of hyperglycemia and hypertriglyceridemia. Furthermore, timing NiAc to feeding resulted in a general downregulation of de novo lipogenesis (DNL) genes in liver. By contrast, NiAc timed to fasting did not reduce tissue lipids, ameliorate glucose intolerance or dyslipidemia, or alter hepatic DNL genes.(Jlr) In conclusion, NiAc dosing regimen has a major impact on metabolic control in obese Zucker rats. Specifically, a well-defined NiAc exposure, timed to feeding periods, profoundly improves the metabolic phenotype of this animal model.
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| 8. |
- Kroon, Tobias
(författare)
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Optimizing nicotinic acid delivery for durable antilipolysis and improved metabolic control
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes is a devastating disease affecting hundreds of millions worldwide. Lipid accumulation in peripheral non-adipose tissues is a major driver of insulin resistance, a central pathophysiological defect of this disease. Plasma free fatty acids (FFA), derived from adipose tissue lipolysis, are an important source of the intracellular lipid pools. Hence, adipose tissue antilipolysis may be an approach for reversing peripheral tissue lipid overload and the down-stream negative consequences, including insulin resistance. Nicotinic acid (NiAc) is a potent inhibitor of adipose lipolysis, acutely reducing plasma FFA concentrations. However, a major FFA rebound occurs upon abrupt NiAc washout and sustained exposures are associated with tolerance development, with FFA returning to pre-dose levels. A key principle of this work was the use of precisely defined plasma NiAc exposure profiles, produced using a programmable, implantable mini-pump. Metabolic consequences of NiAc-induced FFA lowering were assessed in a translationally relevant preclinical model of the metabolic syndrome, the obese Zucker rat. A feedback turnover model adequately described acute FFA responses to NiAc. This model aided in designing a gradual NiAc termination protocol which minimized FFA rebound. The strategy of around-the-clock exposure failed to deliver sustained FFA lowering, due to tolerance development. By contrast, an intermittent strategy succeeded in preserving acute FFA lowering and insulin sensitizing effects. A more complex model was required in order to capture the development of complete tolerance in response to sustained NiAc exposure. Further experiments revealed that NiAc timed to feeding decreased triglycerides in liver and heart and reduced plasma fructosamine. During an oral glucose tolerance test, plasma FFA levels were reduced with amelio¬ration of hyperglycemia and hypertriglyceridemia. By contrast, NiAc timed to fasting did not reduce tissue lipids, ameliorate glucose intolerance or dyslipidemia. In conclusion, the NiAc exposure profile has a major influence on metabolic control. A macro-pharmacologic approach succeed in identifying a rational NiAc delivery profile that suppressed rebound and tolerance and profoundly improved metabolic control in obese Zucker rats. The work shows the power of a multi-disciplinary drug discovery approach, using a comprehensive understanding of the relationship between pharmacokinetics and pharmacodynamics combined with knowledge of metabolic physiology.
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| 9. |
- Kroon, Tobias, et al.
(författare)
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PPARγ and PPARα synergize to induce robust browning of white fat in vivo
- 2020
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Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 36
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Peroxisome proliferator-activated receptors (PPARs) are key transcription factors that regulate adipose development and function, and the conversion of white into brown-like adipocytes. Here we investigated whether PPARα and PPARγ activation synergize to induce the browning of white fat. Methods: A selection of PPAR activators was tested for their ability to induce the browning of both mouse and human white adipocytes in vitro, and in vivo in lean and obese mice. Results: All dual PPARα/γ activators tested robustly increased uncoupling protein 1 (Ucp1) expression in both mouse and human adipocytes in vitro, with tesaglitazar leading to the largest Ucp1 induction. Importantly, dual PPARα/γ activator tesaglitazar strongly induced browning of white fat in vivo in both lean and obese male mice at thermoneutrality, greatly exceeding the increase in Ucp1 observed with the selective PPARγ activator rosiglitazone. While selective PPARγ activation was sufficient for the conversion of white into brown-like adipocytes in vitro, dual PPARα/γ activation was superior to selective PPARγ activation at inducing white fat browning in vivo. Mechanistically, the superiority of dual PPARα/γ activators is mediated at least in part via a PPARα-driven increase in fibroblast growth factor 21 (FGF21). Combined treatment with rosiglitazone and FGF21 resulted in a synergistic increase in Ucp1 mRNA levels both in vitro and in vivo. Tesaglitazar-induced browning was associated with increased energy expenditure, enhanced insulin sensitivity, reduced liver steatosis, and an overall improved metabolic profile compared to rosiglitazone and vehicle control groups. Conclusions: PPARγ and PPARα synergize to induce robust browning of white fat in vivo, via PPARγ activation in adipose, and PPARα-mediated increase in FGF21. © 2020 The Authors
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