Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands; and Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada
...Long-chain fatty acids and lipids serve a wide variety of functions in mammalian homeostasis, particularly in the formation and dynamic properties of biological membranes and as fuels for energy production in tissues such as heart and skeletal muscle. On the other hand, long-chain fatty acid metabolites may exert toxic effects on cellular functions and cause cell injury. Therefore, fatty acid uptake into the cell and intracellular handling need to be carefully controlled. In the last few years, our knowledge of the regulation of cellular fatty acid uptake has dramatically increased. Notably, fatty acid uptake was found to occur by a mechanism that resembles that of cellular glucose uptake. Thus, following an acute stimulus, particularly insulin or muscle contraction, specific fatty acid transporters translocate from intracellular stores to the plasma membrane to facilitate fatty acid uptake, just as these same stimuli recruit glucose transporters to increase glucose uptake. This regulatory mechanism is important to clear lipids from the circulation postprandially and to rapidly facilitate substrate provision when the metabolic demands of heart and muscle are increased by contractile activity. Studies in both humans and animal models have implicated fatty acid transporters in the pathogenesis of diseases such as the progression of obesity to insulin resistance and type 2 diabetes. As a result, membrane fatty acid transporters are now being regarded as a promising therapeutic target to redirect lipid fluxes in the body in an organ-specific fashion.
The widely expressed transmembrane glycoprotein, cluster of differentiation 36 (CD36), a scavenger receptor class B protein (SR-B2), serves many functions in lipid metabolism and signaling. Here, we ...review CD36's role in facilitating cellular long-chain fatty acid uptake across the plasma membrane, particularly in heart and skeletal muscles. CD36 acts in concert with other membrane proteins, such as peripheral plasma membrane fatty acid-binding protein, and is an intracellular docking site for cytoplasmic fatty acid-binding protein. The cellular fatty-acid uptake rate is governed primarily by the presence of CD36 at the cell surface, which is regulated by the subcellular vesicular recycling of CD36 from endosomes to the plasma membrane. CD36 has been implicated in dysregulated fatty acid and lipid metabolism in pathophysiological conditions, particularly in high-fat diet-induced insulin resistance and diabetic cardiomyopathy. Current research is exploring signaling pathways and vesicular trafficking routes involving CD36 to identify metabolic targets to manipulate the cellular utilization of fatty acids. Because of its rate-controlling function in the use of fatty acids in the heart and muscle, CD36 would be a preferable target to protect myocytes against lipotoxicity. Despite a poor understanding of its mechanism of action, CD36 has emerged as a pivotal membrane protein involved in whole-body lipid homeostasis.
Background:mTOR upregulation has been reported to be involved in the pathogenesis of thyroid tumors and treatment with the mTOR inhibitor everolimus has shown promising results in endocrine tumors. ...We conducted a prospective phase II clinical trial to determine the efficacy and safety of everolimus in patients with advanced differentiated thyroid cancer.Patients and methods:Twenty-eight patients with progressive metastatic or locally advanced radioactive refractory differentiated thyroid cancer and 7 patients with anaplastic thyroid cancer were included and received everolimus 10mg orally once daily. The primary endpoint was disease control rate (complete (CR) + partial response (PR) + stable disease (SD) >24 weeks). Secondary endpoints included progression free survival (PFS), overall survival (OS), toxicity, mutational related outcomes and pharmacokinetic related outcomes (PK).Results:Median follow-up duration was 38 months (2-64). Seventeen patients (65%) showed SD, of which 15 (58%) showed SD > 24 weeks. No CR or PR were observed. Median PFS and OS were 9 (95%CI:4-14) and 18 (95%CI:7-29) months, respectively. Survival was negatively influenced by the presence of bone metastases. Toxicity was predominantly grade 1/2 and included anemia (64%), cough (64%), stomatitis (61%) and hyperglycemia (61%). Duration of SD was related to everolimus exposure. The presence of somatic gene variants related to mTOR signaling did not clearly stratify for responses.Conclusion:Everolimus has clinically relevant antitumor activity in patients with advanced differentiated thyroid cancer. Given the observed disease control rate and the relatively low toxicity profile, further investigation of everolimus in sequential or combination therapy in these patients is warranted.
Liquid manipulation is the foundation of most laboratory processes. For macroscale liquid handling, both do-it-yourself and commercial robotic systems are available; however, for microscale, reagents ...are expensive and sample preparation is difficult. Over the last decade, lab-on-a-chip (LOC) systems have come to serve for microscale liquid manipulation; however, lacking automation and multi-functionality. Despite their potential synergies, each has grown separately and no suitable interface yet exists to link macro-level robotics with micro-level LOC or microfluidic devices. Here, we present a robot-assisted acoustofluidic end effector (RAEE) system, comprising a robotic arm and an acoustofluidic end effector, that combines robotics and microfluidic functionalities. We further carried out fluid pumping, particle and zebrafish embryo trapping, and mobile mixing of complex viscous liquids. Finally, we pre-programmed the RAEE to perform automated mixing of viscous liquids in well plates, illustrating its versatility for the automatic execution of chemical processes.
The molecular mechanisms underlying the cellular uptake of long-chain fatty acids and the regulation of this process have been elucidated in appreciable detail in the last decades. Two main players ...in this field, each discovered in the early 1990s, are (i) a membrane-associated protein first identified in adipose (‘fat’) tissue and referred to as putative fatty acid translocase (FAT)/CD36 (now officially designated as SR-B2) which facilitates the transport of fatty acids across the plasma membrane, and (ii) the family of transcription factors designated peroxisome proliferator-activated receptors (PPARα, PPARγ, and PPARβ/δ) for which fatty acids and fatty acid metabolites are the preferred ligand. CD36/SR-B2 is the predominant membrane protein involved in fatty acid uptake into intestinal enterocytes, adipocytes and cardiac and skeletal myocytes. The rate of cellular fatty acid uptake is regulated by the subcellular vesicular recycling of CD36/SR-B2 from endosomes to the plasma membrane. Fatty acid-induced activation of PPARs results in the upregulation of the expression of genes encoding various proteins and enzymes involved in cellular fatty acid utilization. Both CD36/SR-B2 and the PPARs have been implicated in the derangements in fatty acid and lipid metabolism occurring with the development of pathophysiological conditions, such as high fat diet-induced insulin resistance and diabetic cardiomyopathy, and have been suggested as targets for metabolic intervention. In this brief review we discuss the discovery and current understanding of both CD36/SR-B2 and the PPARs in metabolic homeostasis.
•The mechanism and regulation of cellular (long-chain) fatty acid uptake has been disclosed in the last two decades.•The membrane protein CD36/SR-B2 facilitates fatty acid uptake in adipose tissue, intestine, heart and skeletal muscle.•Short-term regulation of fatty acid uptake involves intracellular recycling of CD36/SR-B2 to and from the plasma membrane.•By binding to PPARs fatty acids upregulate the expression of genes of cellular lipid utilization including CD36/SR-B2.•Dr. Paul Grimaldi has made seminal contributions to disclosing both the function of CD36/SR-B2 and that of PPARβ/δ.
•The endocannabinoids anandamide (AEA) and 2-arachidonoylglyerol (2-AG) are endogenous lipid mediators with a short life span that exert paracrine or autocrine signaling.•The endocannabinoid system ...is a ubiquitous cell signaling system that serves various protective roles in pathophysiological conditions.•Modulation of the endocannabinoid system may be an effective approach to alter cellular metabolism.
The endocannabinoids anandamide (AEA) and 2-arachidonoylglyerol (2-AG) are endogenous lipid mediators that exert protective roles in pathophysiological conditions, including cardiovascular diseases. In this brief review, we provide a conceptual framework linking endocannabinoid signaling to the control of the cellular and molecular hallmarks, and categorize the key components of endocannabinoid signaling that may serve as targets for novel therapeutics. The emerging picture not only reinforces endocannabinoids as potent regulators of cellular metabolism but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought.
We aimed to assess the association between metabolic syndrome (MS) and hepatitis B/C virus infection using a large population-based study.
A population-based cross-sectional study design was adopted ...with a total of 53,528 subjects being enrolled from the integrated multiple diseases screening program in Keelung, Taiwan. Evidence of past hepatitis B/C infection, acquired during childhood or as a young adult, was identified during the two-stage liver cancer screening part of the process. Information on biochemical markers and anthropometric measures related to MS, such as fasting blood sugar, triglyceride and high-density lipoprotein (HDL), abdominal circumference and blood pressure (BP), were collected routinely while screening for hypertension, type 2 diabetes, and hyperlipidemia. Logistic regression was used to estimate odds ratios and related 95% confidence intervals for the associations between MS and hepatitis B/C infection.
High blood pressure (SBP > or = 135 mmHg or DBP > or = 85 mmHg) (adjusted odd ratio: 0.89 (0.83-0.94)) and high triglyceride (> or = 150 mg/dl) (adjusted odds ratio: 0.65 (0.60-0.69)) were, after adjusting for gender and age, inversely associated with being HBsAg positive (P<0.05). The likelihood of developing MS was lower in the HBsAg positive than the HBsAg negative (adjusted odds ratio: 0.84 (0.76-0.93)). A positive association between being anti-HCV positive and having low serum HDL (male <40 mg/dl, female <50 mg/dl) was also noted (adjusted odds ratio: 1.61 (1.37-1.88) after controlling for gender and age). High triglyceride was inversely associated with being anti-HCV positive (adjusted odds ratio: 0.63 (0.55-0.71).
There is an inverse association between MS and hepatitis B virus infection whereas the association was heterogeneous for HCV infection with a positive association with abnormal serum HDL but an inverse association with hypertriglyceridemia.
Summary
Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO‐incompatible (ABOi) kidney transplantation with ...matched ABO‐compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. We performed a retrospective study with propensity matching and compared patient and death‐censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. 296 ABOi were compared with 1184 center and propensity‐matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group, and PRA). Patient survival was better compared with deceased donor hazard ratio (HR) for death of HR 0.69 (0.49–0.96) and non‐significantly different from ABOc living donor recipients HR 1.28 (0.90–1.81). Rate of graft failure was higher compared with ABOc living donor transplantation HR 2.63 (1.72–4.01). Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab‐treated recipients (P < 0.001). ABOi kidney transplantation is superior to deceased donor transplantation. Rejection rate and graft failure are higher compared with matched ABOc living donor transplantation, underscoring the need for further studies into risk stratification and induction therapy NTR7587, www.trialregister.nl.
ABO‐incompatible kidney transplantation has better patient survival than matched deceased donor transplantation, however with inferior graft survival as compared to matched living donor ABO‐compatible transplantation. Rejection rates differ according to induction therapy, and graft survival differs according to blood group titers.
Expression of programmed cell death-ligand 1 (PD-L1) is being used as predictive biomarker for immunotherapy in head and neck squamous cell carcinoma (HNSCC). Several antibodies are available for ...PD-L1 testing and multiple staining and scoring methods are used. This study aimed to compare the performance of two PD-L1 standardized assays (SP263 and 22C3 pharmDx) and one laboratory-developed test (LDT) (22C3) in HNSCC using the tumor proportion score (TPS) and the combined positive score (CPS). Pretreatment biopsies from 147 HNSCC patients were collected in a tissue-microarray (TMA). Serial sections of the TMA were immunohistochemically stained for PD-L1 expression using 22C3 pharmDx on the Dako Link 48 platform, SP263 on the Ventana Benchmark Ultra platform, and 22C3 as an LDT on the Ventana Benchmark Ultra. Stained slides were assessed for TPS and CPS. Cutoffs of ≥1% and ≥50% for TPS and ≥1 and ≥20 for CPS were used. Concordance between the different staining assays was moderate to poor for TPS (intraclass correlation coefficient (ICC) 0.46) as well as for CPS (ICC 0.34). When stratifying patients by clinically relevant cutoffs, considerable differences between the assays were observed: concordance was poor for both TPS and CPS. Generally, SP263 stained a higher percentage of cells than the other assays, especially when using the CPS. Moderate concordance was shown between three different PD-L1 immunohistochemical assays and considerable differences in PD-L1 positivity were observed when using clinically relevant cutoffs. This should be taken into account when using PD-L1 expression to guide clinical practice.
Aims/hypothesis
The mechanisms for diet-induced intramyocellular lipid accumulation and its association with insulin resistance remain contentious. In a detailed time-course study in rats, we ...examined whether a high-fat diet increased intramyocellular lipid accumulation via alterations in fatty acid translocase (FAT/CD36)-mediated fatty acid transport, selected enzymes and/or fatty acid oxidation, and whether intramyocellular lipid accretion coincided with the onset of insulin resistance.
Methods
We measured, daily (on days 1–7) and/or weekly (for 6 weeks), the diet-induced changes in circulating substrates, insulin, sarcolemmal substrate transporters and transport, selected enzymes, intramyocellular lipids, mitochondrial fatty acid oxidation and basal and insulin-stimulated sarcolemmal GLUT4 and glucose transport. We also examined whether upregulating fatty acid oxidation improved glucose transport in insulin-resistant muscles. Finally, in
Cd36
-knockout mice, we examined the role of FAT/CD36 in intramyocellular lipid accumulation, insulin sensitivity and diet-induced glucose intolerance.
Results
Within 2–3 days, diet-induced increases occurred in insulin, sarcolemmal FAT/CD36 (but not fatty acid binding protein FABPpm or fatty acid transporter FATP1 or 4), fatty acid transport and intramyocellular triacylglycerol, diacylglycerol and ceramide, independent of enzymatic changes or muscle fatty acid oxidation. Diet-induced increases in mitochondria and mitochondrial fatty acid oxidation and impairments in insulin-stimulated glucose transport and GLUT4 translocation occurred much later (≥21 days). FAT/CD36 ablation impaired insulin-stimulated fatty acid transport and lipid accumulation, improved insulin sensitivity and prevented diet-induced glucose intolerance. Increasing fatty acid oxidation in insulin-resistant muscles improved glucose transport.
Conclusions/interpretations
High-fat feeding rapidly increases intramyocellular lipids (in 2–3 days) via insulin-mediated upregulation of sarcolemmal FAT/CD36 and fatty acid transport. The 16–19 day delay in the onset of insulin resistance suggests that additional mechanisms besides intramyocellular lipids contribute to this pathology.
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