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1.
Unfolded Protein Response: Cause or Consequence of Lipid and Lipoprotein Metabolism Disturbances?
Pinto, BAS, França, LM, Laurindo, FRM, Paes, AMA
Advances in experimental medicine and biology. 2019;:67-82
Abstract
The liver plays a capital role in the control of whole body energy homeostasis through the metabolization of dietary carbohydrates and lipids. However, under excess macronutrient uptake, those pathways overcharge nucleus-to-endoplasmic reticulum (ER) traffic pathways, leading to luminal overload of unfolded proteins which activates a series of adaptive signaling pathways known as unfolded protein response (UPR). The UPR is a central network mechanism for cellular stress adaptation, however far from a global nonspecific all-or-nothing response. Such a complex signaling network is able to display considerable specificity of responses, with activation of specific signaling branches trimmed for distinct types of stimuli. This makes the UPR a fundamental mechanism underlying metabolic processes and diseases, especially those related to lipid and carbohydrate metabolism. Thus, for a better understanding of the role of UPR on the physiopathology of lipid metabolism disorders, the concepts discussed along this chapter will demonstrate how several metabolic derangements activate UPR components and, in turn, how UPR triggers several metabolic adaptations through its component signaling proteins. This dual role of UPR on lipid metabolism will certainly foment the pursuit of an answer for the question: is UPR cause or consequence of lipid and lipoprotein metabolism disturbances?
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Familial Hypercholesterolemia and Lipoprotein Apheresis.
Makino, H, Koezuka, R, Tamanaha, T, Ogura, M, Matsuki, K, Hosoda, K, Harada-Shiba, M
Journal of atherosclerosis and thrombosis. 2019;(8):679-687
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Abstract
Lipoprotein apheresis has been developed as the treatment for refractory familial hypercholesterolemia (FH) to remove low-density lipoprotein (LDL), which is the main pathogenic factor. Currently, three procedures are available in Japan, including the plasma exchange, double-membrane filtration, and selective LDL adsorption. Selective LDL adsorption, which was developed in Japan, has been one of the most common treatment methods in the world. Lipoprotein apheresis enabled the prevention of atherosclerosis progression even in homozygous FH (HoFH) patients. However, in our observational study, HoFH patients who started lipoprotein apheresis in adulthood had a poorer prognosis than those who started in childhood. Therefore, HoFH patients need to start lipoprotein apheresis as early as possible. Although the indication for lipoprotein apheresis in heterozygous FH (HeFH) patients has been decreasing with the advent of strong statins, our observational study showed that HeFH patients who discontinued lipoprotein apheresis had a poorer prognosis than patients who continued apheresis therapy. These results suggest that it is beneficial for very-high-risk HeFH patients to be treated by lipoprotein apheresis even if their LDL cholesterol is controlled well by lipid-lowering agents. Since launching a new class of lipid-lowering agents, proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and microsome triglyceride transfer protein inhibitors, the indication for lipoprotein apheresis in FH has been changing. However, despite the development of these drugs, lipoprotein apheresis is still an option with a high therapeutic effect for FH patients with severe atherosclerotic cardiovascular disease.
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3.
Current Role of Lipoprotein Apheresis.
Thompson, G, Parhofer, KG
Current atherosclerosis reports. 2019;(7):26
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Abstract
PURPOSE OF REVIEW Lipoprotein apheresis is a very efficient but time-consuming and expensive method of lowering levels of low-density lipoprotein cholesterol, lipoprotein(a)) and other apoB containing lipoproteins, including triglyceride-rich lipoproteins. First introduced almost 45 years ago, it has long been a therapy of "last resort" for dyslipidaemias that cannot otherwise be managed. In recent years new, very potent lipid-lowering drugs have been developed and the purpose of this review is to define the role of lipoprotein apheresis in the current setting. RECENT FINDINGS Lipoprotein apheresis still plays an important role in managing patients with homozygous FH and some patients with other forms of hypercholesterolaemia and cardiovascular disease. In particular, patients not achieving treatment goals despite modern lipid-lowering drugs, either because these are not tolerated or the response is insufficient. Recently, lipoprotein(a) has emerged as an important cardiovascular risk factor and lipoprotein apheresis has been used to decrease lipoprotein(a) concentrations in patients with marked elevations and cardiovascular disease. However, there is considerable heterogeneity concerning the recommendations by scientific bodies as to which patient groups should be treated with lipoprotein apheresis. Lipoprotein apheresis remains an important tool for the management of patients with severe drug-resistant dyslipidaemias, especially those with homozygous FH.
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Remnant lipoproteins and atherosclerotic cardiovascular disease.
Tada, H, Nohara, A, Inazu, A, Mabuchi, H, Kawashiri, MA
Clinica chimica acta; international journal of clinical chemistry. 2019;:1-5
Abstract
Lipoproteins are one of the major risk factors for atherosclerotic cardiovascular disease (ASCVD), among which, low-density lipoprotein (LDL) particles have been definitively shown to be causally associated with the development of ASCVD. Additionally, the concept of remnant lipoproteins has emerged as lipoprotein metabolism has been fully investigated. The principal concept of this lipoprotein category is triglyceride-rich lipoproteins significantly increase at the postprandial state. Although there is no clear definition of remnant lipoproteins, they typically include chylomicron remnants, which are lipolyzed particles from chylomicron, as well as very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) remnants that are lipolyzed particles from VLDL and IDL particles. However, the most important factor of these lipoproteins is such remnant lipoproteins seem to be causally associated with ASCVD, independent of LDL particles or LDL cholesterol. It has been challenging to assert a causal association of remnant lipoproteins and ASCVD; however, accumulated evidence from epidemiological studies, as well as recent Mendelian randomization studies from common and rare genetic variations strongly support this association. In this article, a basic explanation of lipoprotein metabolism is presented, including remnant lipoproteins and the important causal associations with ASCVD from a clinical point of view.
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Discovery of bioactive nitrated lipids and nitro-lipid-protein adducts using mass spectrometry-based approaches.
Melo, T, Montero-Bullón, JF, Domingues, P, Domingues, MR
Redox biology. 2019;:101106
Abstract
Nitro-fatty acids (NO2-FA) undergo reversible Michael adduction reactions with cysteine and histidine residues leading to the post-translational modification (PTM) of proteins. This electrophilic character of NO2-FA is strictly related to their biological roles. The NO2-FA-induced PTM of signaling proteins can lead to modifications in protein structure, function, and subcellular localization. The nitro lipid-protein adducts trigger a series of downstream signaling events that culminates with anti-inflammatory, anti-hypertensive, and cytoprotective effects mediated by NO2-FA. These lipoxidation adducts have been detected and characterized both in model systems and in biological samples by using mass spectrometry (MS)-based approaches. These MS approaches allow to unequivocally identify the adduct together with the targeted residue of modification. The identification of the modified proteins allows inferring on the possible impact of the NO2-FA-induced modification. This review will focus on MS-based approaches as valuable tools to identify NO2-FA-protein adducts and to unveil the biological effect of this lipoxidation adducts.
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Endoplasmic reticulum quality control in lipoprotein metabolism.
Koerner, CM, Roberts, BS, Neher, SB
Molecular and cellular endocrinology. 2019;:110547
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Abstract
Lipids play a critical role in energy metabolism, and a suite of proteins is required to deliver lipids to tissues. Several of these proteins require an intricate endoplasmic reticulum (ER) quality control (QC) system and unique secondary chaperones for folding. Key examples include apolipoprotein B (apoB), which is the primary scaffold for many lipoproteins, dimeric lipases, which hydrolyze triglycerides from circulating lipoproteins, and the low-density lipoprotein receptor (LDLR), which clears cholesterol-rich lipoproteins from the circulation. ApoB requires specialized proteins for lipidation, dimeric lipases lipoprotein lipase (LPL) and hepatic lipase (HL) require a transmembrane maturation factor for secretion, and the LDLR requires several specialized, domain-specific chaperones. Deleterious mutations in these proteins or their chaperones may result in dyslipidemias, which are detrimental to human health. Here, we review the ER quality control systems that ensure secretion of apoB, LPL, HL, and LDLR with a focus on the specialized chaperones required by each protein.
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The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk.
Sandesara, PB, Virani, SS, Fazio, S, Shapiro, MD
Endocrine reviews. 2019;(2):537-557
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Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is a well-established mediator of atherosclerosis and a key target for intervention for the primary and secondary prevention of ASCVD. However, despite substantial reduction in LDL-C, patients continue to have recurrent ASCVD events. Hypertriglyceridemia may be an important contributor of this residual risk. Observational and genetic epidemiological data strongly support a causal role of triglycerides (TGs) and the cholesterol content within triglyceride-rich lipoproteins (TGRLs) and/or remnant cholesterol (RC) in the development of ASCVD. TGRLs are composed of hepatically derived very low-density lipoprotein and intestinally derived chylomicrons. RC is the cholesterol content of all TGRLs and plasma TGs serve as a surrogate measure of TGRLs and RC. Although lifestyle modification remains the cornerstone for management of hypertriglyceridemia, many novel drugs are in development and have shown impressive efficacy in lowering TG levels. Several ongoing, randomized controlled trials are underway to examine the impact of these novel agents on ASCVD outcomes. In this comprehensive review, we provide an overview of the biology, epidemiology, and genetics of TGs and ASCVD; we discuss current and novel TG-lowering therapies under development.
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Clinical features and genetic analysis of childhood sitosterolemia: Two case reports and literature review.
Huang, D, Zhou, Q, Chao, YQ, Zou, CC
Medicine. 2019;(15):e15013
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Abstract
RATIONALE Sitosterolemia is a rare autosomal recessive disorder of dyslipidemia due to mutations of genes ABCG5 and ABCG8, leading to highly elevated plasma levels of plant sterols and expanded body pools of cholesterol. PATIENT CONCERNS We present a 9-year-old and a 7-year-old Chinese boy with hypercholesterolemia and xanthomas of sitosterolemia due to ABCG5 gene mutations. We also make a literature review of another 30 sitosterolemic children cases that have been reported with virulence ABCG5 gene mutations. DIAGNOSIS We took peripheral blood samples from 2 patients and their parents to conduct genetic analysis by next-generation sequencing (NGS) technologies. INTERVENTIONS The 2 patients received dietary modifications without pharmaceuticals treatment. OUTCOMES A c.1166G>A (Arg389His) homozygosis mutation in exon 9 was observed in case 1, whereas a c.751C>T (Gln251*) homozygosis mutation in exon 6 was found in case 2. Literature review found another 30 pediatric cases with sitosterolemia due to ABCG5 gene mutation. The lipid profile was normalized and xanthomas got smaller with combined therapy of a combined low-cholesterol and low-phytosterols diet. LESSONS These suggested that in patients (especially Asian patients) with multiple xanthomas, severe hypercholesterolemia, or elevated low-density lipoprotein-cholesterol, sitosterolemia should be considered in the differential diagnosis. Early diagnosis is important, and restriction of both cholesterol and phytosterols diet should suggested for these patients.
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9.
Flavin transferase: the maturation factor of flavin-containing oxidoreductases.
Bogachev, AV, Baykov, AA, Bertsova, YV
Biochemical Society transactions. 2018;(5):1161-1169
Abstract
Flavins, cofactors of many enzymes, are often covalently linked to these enzymes; for instance, flavin adenine mononucleotide (FMN) can form a covalent bond through either its phosphate or isoalloxazine group. The prevailing view had long been that all types of covalent attachment of flavins occur as autocatalytic reactions; however, in 2013, the first flavin transferase was identified, which catalyzes phosphoester bond formation between FMN and Na+-translocating NADHquinone oxidoreductase in certain bacteria. Later studies have indicated that this post-translational modification is widespread in prokaryotes and is even found in some eukaryotes. Flavin transferase can occur as a separate ∼40 kDa protein or as a domain within the target protein and recognizes a degenerate DgxtsAT/S motif in various target proteins. The purpose of this review was to summarize the progress already achieved by studies of the structure, mechanism, and specificity of flavin transferase and to encourage future research on this topic. Interestingly, the flavin transferase gene (apbE) is found in many bacteria that have no known target protein, suggesting the presence of yet unknown flavinylation targets.
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Relevance of human fat distribution on lipid and lipoprotein metabolism and cardiovascular disease risk.
Piché, ME, Vasan, SK, Hodson, L, Karpe, F
Current opinion in lipidology. 2018;(4):285-292
Abstract
PURPOSE OF REVIEW Upper body abdominal and lower body gluteofemoral fat depot masses display opposing associations with plasma lipid and lipoprotein and cardiovascular disease (CVD) risk profiles. We review developments on adipose tissue fatty acid metabolism in the context of body fat distribution and how that might be related to adverse lipid and lipoprotein profiles and CVD risk. RECENT FINDINGS Recent data have confirmed the paradoxical relationship of upper abdominal and lower body gluteofemoral adiposity and CVD risk. Mechanistically, this is likely to reflect the different ways fat depots handle lipid storage and release, which impacts directly and indirectly on lipid and lipoprotein metabolism. The upper body enhances immediate fat storage pathway with rapid uptake of dietary-derived fatty acids, whereas the lower body fat depot has a reduced lipid turnover accommodating a slower fat redistribution. Body fat distribution and the fat depots' ability to undergo appropriate expansion when fat storage is required, rather than overall body fatness, appear as the important determinant of metabolic health. SUMMARY A focus on fat distribution in overweight people, preferably using precise imaging methods, rather than quantifying total body fatness, is likely to provide the medical community with better tools to stratify and treat patients with obesity-related complications.