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1.
High-density lipoproteins (HDL): Novel function and therapeutic applications.
Darabi, M, Kontush, A
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2022;(1):159058
Abstract
The failure of high-density lipoprotein (HDL)-raising agents to reduce cardiovascular disease (CVD) together with recent findings of increased cardiovascular mortality in subjects with extremely high HDL-cholesterol levels provide new opportunities to revisit our view of HDL. The concept of HDL function developed to explain these contradictory findings has recently been expanded by a role played by HDL in the lipolysis of triglyceride-rich lipoproteins (TGRLs) by lipoprotein lipase. According to the reverse remnant-cholesterol transport (RRT) hypothesis, HDL critically contributes to TGRL lipolysis via acquirement of surface lipids, including free cholesterol, released from TGRL. Ensuing cholesterol transport to the liver with excretion into the bile may reduce cholesterol influx in the arterial wall by accelerating removal from circulation of atherogenic, cholesterol-rich TGRL remnants. Such novel function of HDL opens wide therapeutic applications to reduce CVD in statin-treated patients, which primarily involve activation of cholesterol flux upon lipolysis.
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Leading the way in the nervous system: Lipid Droplets as new players in health and disease.
Teixeira, V, Maciel, P, Costa, V
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2021;(1):158820
Abstract
Lipid droplets (LDs) are ubiquitous fat storage organelles composed of a neutral lipid core, comprising triacylglycerols (TAG) and sterol esters (SEs), surrounded by a phospholipid monolayer membrane with several decorating proteins. Recently, LD biology has come to the foreground of research due to their importance for energy homeostasis and cellular stress response. As aberrant LD accumulation and lipid depletion are hallmarks of numerous diseases, addressing LD biogenesis and turnover provides a new framework for understanding disease-related mechanisms. Here we discuss the potential role of LDs in neurodegeneration, while making some predictions on how LD imbalance can contribute to pathophysiology in the brain.
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Sex Differences in Adipose Tissue Function.
Gavin, KM, Bessesen, DH
Endocrinology and metabolism clinics of North America. 2020;(2):215-228
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Abstract
Regional adipose tissue distribution differs between men and women. Differences in the accumulation of adipose tissue as well as the regulation of secretion of a number of products from adipose tissue are under the control of sex steroids, which act through a wide variety of mechanisms, both direct and indirect, to tailor metabolism to the unique needs of each sex. A fuller understanding of sex-based differences in adipose tissue function may help with tailored strategies for disease prevention and treatment and provide insights into fundamental differences in the processes that regulate nutrient homeostasis and body weight.
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Non-adrenergic control of lipolysis and thermogenesis in adipose tissues.
Braun, K, Oeckl, J, Westermeier, J, Li, Y, Klingenspor, M
The Journal of experimental biology. 2018;(Pt Suppl 1)
Abstract
The enormous plasticity of adipose tissues, to rapidly adapt to altered physiological states of energy demand, is under neuronal and endocrine control. In energy balance, lipolysis of triacylglycerols and re-esterification of free fatty acids are opposing processes operating in parallel at identical rates, thus allowing a more dynamic transition from anabolism to catabolism, and vice versa. In response to alterations in the state of energy balance, one of the two processes predominates, enabling the efficient mobilization or storage of energy in a negative or positive energy balance, respectively. The release of noradrenaline from the sympathetic nervous system activates lipolysis in a depot-specific manner by initiating the canonical adrenergic receptor-Gs-protein-adenylyl cyclase-cyclic adenosine monophosphate-protein kinase A pathway, targeting proteins of the lipolytic machinery associated with the interface of the lipid droplets. In brown and brite adipocytes, lipolysis stimulated by this signaling pathway is a prerequisite for the activation of non-shivering thermogenesis. Free fatty acids released by lipolysis are direct activators of uncoupling protein 1-mediated leak respiration. Thus, pro- and anti-lipolytic mediators are bona fide modulators of thermogenesis in brown and brite adipocytes. In this Review, we discuss adrenergic and non-adrenergic mechanisms controlling lipolysis and thermogenesis and provide a comprehensive overview of pro- and anti-lipolytic mediators.
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5.
Hydrogen Sulfide in the Adipose Tissue-Physiology, Pathology and a Target for Pharmacotherapy.
Bełtowski, J, Jamroz-Wiśniewska, A
Molecules (Basel, Switzerland). 2016;(1)
Abstract
Hydrogen sulfide (H₂S) is synthesized in the adipose tissue mainly by cystathionine γ-lyase (CSE). Several studies have demonstrated that H₂S is involved in adipogenesis, that is the differentiation of preadipocytes to adipocytes, most likely by inhibiting phosphodiesterases and increasing cyclic AMP concentration. The effect of H₂S on adipose tissue insulin sensitivity and glucose uptake is controversial. Some studies suggest that H₂S inhibits insulin-induced glucose uptake and that excess of H₂S contributes to adipose tissue insulin resistance in metabolic syndrome. In contrast, other studies have demonstrated that H₂S stimulates glucose uptake and its deficiency contributes to insulin resistance. Similarly, the effect of H₂S on adipose tissue lipolysis is controversial. H₂S produced by perivascular adipose tissue decreases vascular tone by activating ATP-sensitive and/or voltage-gated potassium channels in smooth muscle cells. Experimental obesity induced by high calorie diet has a time dependent effect on H₂S in perivascular adipose tissue; short and long-term obesity increase and decrease H₂S production, respectively. Hyperglycemia has been consistently demonstrated to suppress CSE-H₂S pathway in various adipose tissue depots. Finally, H₂S deficiency may contribute to adipose tissue inflammation associated with obesity/metabolic syndrome.
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A review of the receptor binding and pharmacological effects of N-methyltyramine.
Stohs, SJ, Hartman, MJ
Phytotherapy research : PTR. 2015;(1):14-6
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Abstract
N-methyltyramine (NMT) is a protoalkaloid isolated from various plant species. It is assumed that NMT is an adrenergic agonist with pharmacological properties similar to other structurally related biogenic amines. Current research studies indicate that NMT is an α-adrenoreceptor antagonist, and exhibits modest inhibitory (antagonistic) activity with respect to the breakdown of fats (lipolysis). Furthermore, NMT has been shown to enhance appetite and digestion of foods through its stimulatory effects on gastrin and pancreatic secretions. As a consequence, NMT is not an ingredient that should be used in dietary supplements designed to promote weight loss. It may result in an increase in perceived energy by promoting appetite and the digestion and absorption of nutrients while inhibiting the breakdown to fats to energy.
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[Molecular mechanisms of modulation of lipolysis in adipose tissue and development of insulinresistance in diabetes].
Ivanov, VV, Shakhristova, EV, Stepovaya, EA, Nosareva, OL, Fedorova, TS, Novitsky, VV
Patologicheskaia fiziologiia i eksperimental'naia terapiia. 2014;(4):111-9
Abstract
Analysis of modern literature data as well as the results of personal research on development of oxidative stress in adipose tissue in diabetes is presented. Mechanisms of modulation of spontaneous and induced lipolysis in adipocytes in conditions of oxidative stress are discussed. Participation of adipose tissue in forming insulin resistance in types 1 and 2 diabetes is considered.
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Regulation of adipocyte lipolysis.
Frühbeck, G, Méndez-Giménez, L, Fernández-Formoso, JA, Fernández, S, Rodríguez, A
Nutrition research reviews. 2014;(1):63-93
Abstract
In adipocytes the hydrolysis of TAG to produce fatty acids and glycerol under fasting conditions or times of elevated energy demands is tightly regulated by neuroendocrine signals, resulting in the activation of lipolytic enzymes. Among the classic regulators of lipolysis, adrenergic stimulation and the insulin-mediated control of lipid mobilisation are the best known. Initially, hormone-sensitive lipase (HSL) was thought to be the rate-limiting enzyme of the first lipolytic step, while we now know that adipocyte TAG lipase is the key enzyme for lipolysis initiation. Pivotal, previously unsuspected components have also been identified at the protective interface of the lipid droplet surface and in the signalling pathways that control lipolysis. Perilipin, comparative gene identification-58 (CGI-58) and other proteins of the lipid droplet surface are currently known to be key regulators of the lipolytic machinery, protecting or exposing the TAG core of the droplet to lipases. The neuroendocrine control of lipolysis is prototypically exerted by catecholaminergic stimulation and insulin-induced suppression, both of which affect cyclic AMP levels and hence the protein kinase A-mediated phosphorylation of HSL and perilipin. Interestingly, in recent decades adipose tissue has been shown to secrete a large number of adipokines, which exert direct effects on lipolysis, while adipocytes reportedly express a wide range of receptors for signals involved in lipid mobilisation. Recently recognised mediators of lipolysis include some adipokines, structural membrane proteins, atrial natriuretic peptides, AMP-activated protein kinase and mitogen-activated protein kinase. Lipolysis needs to be reanalysed from the broader perspective of its specific physiological or pathological context since basal or stimulated lipolytic rates occur under diverse conditions and by different mechanisms.
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Lipolysis of triglyceride-rich lipoproteins, vascular inflammation, and atherosclerosis.
Schwartz, EA, Reaven, PD
Biochimica et biophysica acta. 2012;(5):858-66
Abstract
Epidemiological and interventional studies have implicated elevated triglyceride-rich lipoprotein (TGRL) levels as a risk factor for cardiovascular disease and vascular inflammation, though the results have not been entirely consistent. This appears particularly relevant in model systems where the lipolysis occurs in the setting of established inflammation (e.g., in pre-existing atherosclerotic plaques), rather than in the tissue capillary beds where lipolysis normally occurs. Two main mechanisms seem to link TGRL lipolysis to vascular inflammation. First, lipolysis of TGRL leaves behind partially lipolyzed remnant particles which are better able to enter the vessel wall than nascent TGRL, have a rate of egress substantially lower than their rate of entry, and contain 5-20 times more cholesterol per particle than LDL. Furthermore, remnants do not require oxidation or other modifications to be phagocytized by macrophages, enhancing foam cell formation. Second, saturated fatty acids and oxidized phospholipids released by lipolysis induce inflammation by activating Toll-like receptors of the innate immune system, via oxidative stress, or by greatly amplifying existing pro-inflammatory signals (caused by subclinical endotoxemia) via mitogen-activated protein kinases. However, n-3 and unbound n-9 unsaturated fatty acids released by lipolysis have anti-inflammatory effects. Thus, the contribution of TGRL lipolysis to inflammation likely depends less on the TGRL concentration than on the balance between pro- and anti-inflammatory factors, and on the setting in which the lipolysis occurs. In the setting of the typical "Western" diet, enriched in saturated and oxidized fatty acids and excessive in size, this balance is likely to be tilted towards increased vascular inflammation and atherosclerosis. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
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Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: molecular mechanisms and therapeutic perspectives.
Menendez, JA
Biochimica et biophysica acta. 2010;(3):381-91
Abstract
Evolving evidence suggest that metabolic requirements for cell proliferation are identical in all normal and cancer cells. HER2 oncogene-overexpressors, a highly aggressive subtype of human cancer cells, constitute one of the best examples of how malignant cells maximize their ability to acquire and metabolize nutrients in a manner conductive to proliferation rather than efficient ATP production. HER2-overexpressors optimize their requirements of rapid cancer cell growth by fine-tuning a double [lipogenic/lipolytic]-edged metabolic sword. On the one edge, HER2 oncogene overexpression triggers redundant signaling cascades to ensure that all the major enzymes involved in de novo fatty acid (FA) synthesis will facilitate aerobic glycolysis instead of oxidative phosphorylation for energy production (Warburg effect). HER2 also establishes a positive bidirectional relationship with the key lipogenic enzyme Fatty Acid Synthase (FASN) that rapidly senses and respond to any disturbance in the flux of lipogenic substrates (e.g. NADPH and acetyl-CoA) and lipogenesis end-products (i.e. palmitate). On the other edge, HER2 overexpression arranges detoxifying mechanisms by upregulating PPARgamma, a well established positive regulator role of adipogenesis and lipid storage in cell types with active lipid metabolism. PPARgamma establishes a lipogenesis/lipolysis joining-point that enables HER2-positive cancer cells to avoid endogenous palmitate toxicity while securing palmitate into fat stores to avoid palmitate feedback on FASN functioning. The ability of HER2 to supercharge lipogenesis (by activating regulatory circuits that activate and fuel the lipogenic enzyme FASN) while averting lipotoxicity (by promoting conversion and storage of excess FAs to triglycerides in a PPARgamma-dependent manner) supports the notion that best adapted cancer phenotypes are addicted to oncogenic lipid metabolism for cell proliferation and survival. It is conceptually attractive to assume that we can crash HER2-driven rapid cell proliferation by inhibiting "motor refueling" (upon blockade of lipogenic enzymes), by losing the "lipolytic brake" (upon blockade of PPARgamma) and/or by sticking the "lipogenic gas pedal" (upon supplementation with dietary FAs).