Extreme Hyperlipidemia Research Articles

N-acetylcysteine attenuates atherosclerosis progression in aging LDL receptor deficient mice with preserved M2 macrophages and increased CD146

Background and aimsInflammation and reactive oxygen species (ROS) are important to the pathogenesis of atherosclerosis. The effect of antioxidants on atherosclerosis is inconsistent, and sometimes controversial. We aimed to test the hypothesis that attenuation of atherosclerosis by N-acetylcysteine (NAC) depends on NAC treatment timing and duration. MethodsMale LDL receptor deficient (LDLR−/−) mice were fed a normal diet (ND) and divided into controls (on ND for 24 months), models 1–2 (at age of 9 months, starting NAC treatment for 3 or 6 months), and model 3 (at age of 18 months, starting NAC treatment for 6 months). To determine if hyperlipidemia compromises NAC treatment outcome, mice were fed a high fat diet (HFD) starting at age of 6 weeks and treated with NAC starting at 9 months of age for 6 months. ResultsNAC treatment for 6 months, not for 3 months, significantly attenuated atherosclerosis progression, but did not reverse atherosclerotic lesions, in aging LDLR−/− mice on ND. NAC had no effect on atherosclerotic lesions in mice on HFD. NAC treatment significantly decreased aortic ROS production, and the levels of inflammatory cytokines in serum and aorta of aging LDLR−/− mice with increased CD146 level. Bone marrow transplantation study with GFP-positive bone marrow cells showed that NAC treatment preserved M2 population and M2 polarization in the aorta of LDLR−/− mice. ConclusionsEarly and adequate NAC treatment could effectively attenuate inflammation and atherosclerosis progression with preserved M2 population and increased CD146 level in aging LDLR−/− mice without extreme hyperlipidemia.

Acquired hypolipoproteinemia and hemophagocytic lymphohistiocytosis: A previously unexplored association?

e19041 Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that is the result of macrophage hyperactivation, leading to disordered cellular phagocytosis that is highly fatal if left untreated. The precise precipitating factor that leads to HLH is presently unknown. Secondary HLH is more common in adults and has numerous causes, including several autoimmune diseases, rheumatological disorders, cancers, and infections. These predisposing conditions are similar in that they are characterized by increased rates of cellular replication and often accompanied by significant oxidative stress. Lipoprotein changes in HLH have not been previously described. Methods: Between August 2018 and June 2020, three cases of secondary HLH were discovered to have profound hypolipoproteinemia with severely reduced total cholesterol, undetectable LDL-C, and extremely depressed HDL-C levels. As a result, a retrospective review of the University of Michigan HLH registry was performed, identifying cases of HLH where full lipid panels were performed as part of their diagnosis and/or treatment between 2012 and 2020. 18 total patients were identified with a confirmed diagnosis of HLH and who had a full lipid panel performed as a part of their diagnostic evaluation. Results: 100% of patients were found to have HDL-C less than 30 mg/dL, consistent with severe HDL-C deficiency, and 84% had HDL-C less than 20 mg/dL. Similarly, 74% of patients were found to have LDL-C < 100 mg/dL, 47% with LDL-C < 50 mg/dL, and 33% had undetectable LDL-C levels. Median total cholesterol was 124 mg/dL, median LDL-C was 35 mg/dL, and median HDL-C was 7 mg/dL. Notably, these reductions were not explained by the observed variability in hypertriglyceridemia, and marked hypertriglyceridemia > 500 mg/dL was not seen in 88% of patients, with a median triglyceride value of 279. Interestingly, one patient displayed an opposite phenotype with extreme hyperlipidemia, with total cholesterol of 727 mg/dL and LDL-C of 658 md/dL. Conclusions: Severe derangements in circulating lipoproteins appear to be a common finding within sHLH.These findings have not been previously described within the context of the disease. Herein, we provide a framework for hypothesizing why HLH may potentially occur in the setting of hypolipidemia. Furthermore, we provide an additional hypothesis that serves to justify why these changes may occur in an evolutionary context.

Case report: Lifesaving therapeutic plasma exchange by cell saver in an obstetric emergency

Introduction. Abnormally high levels of triglycerides (hyperlipidemia) are often the result of a number of disorders in the body, which over time can lead to conditions such as hypothyroidism, nephrotic syndrome, diabetes, obstruction of the biliary ducts, hepatic impairment et al. The topic of how to treat the extreme hyperlipidemia has been an important discussion point in medical circles. Case report. This paper presents the case of a 33-year-old pregnant women in the 34th week of the first proper pregnancy with laboratory-verified extreme hyperlipidemia, who was brought in critical condition to the Clinical Center of Kragujevac. After the emergency cesarean section was performed, due to the general poor condition of the patient and extremely high levels of triglycerides and cholesterol, lipopheresis was indicated, which in our institution was not technically possible to treat and therefore it was necessary to find an alternative solution. Conclusion. It was shown that the application of intraoperative blood salvage can be used successfully not only in heavy bleeding during surgery, but also for cleaning the blood itself, which was clearly shown in the laboratory analysis.

A Teenaged Patient with Severe Asparaginase-Induced Hypertriglyceridemia Safely Re-Challenged During Primary and Relapse Therapy for Acute Lymphoblastic Leukemia

Asparaginase is a highly effective drug in the management of acute lymphoblastic leukemia (ALL), but can cause abnormalities in lipid metabolism leading to hypercholesterolemia and hypertriglyceridemia. This may result in serious consequences, such as pancreatitis and hyperviscosity syndrome. Currently, there is no consensus regarding re-challenge with further doses of asparaginase if this complication occurs. We report the case of a teenaged male patient with ALL treated with asparaginase who presented with extreme hyperlipidemia during induction therapy. He was managed conservatively with complete resolution of lipid abnormalities and was re-challenged during both primary and relapse therapy without a recurrence of hyperlipidemia.

Gestational hyperlipidemia and acute pancreatitis with underlying partial lipoprotein lipase deficiency and apolipoprotein E3/E2 genotype

We report the case of a patient who experienced extreme recurrent gestational hyperlipidemia. She was diagnosed with partial lipoprotein lipase (LPL) deficiency but without an associated LPL gene mutation in the presence of the apolipoprotein E3/2 genotype. This is the first reported case of extreme gestational hyperlipidemia with a partial LPL deficiency in the absence of an LPL gene mutation and the apolipoprotein E 3/2 genotype. She was managed with strict dietary control and medicated with omega-3 acid ethyl esters. A patient with extreme hyperlipidemia that is limited to the gestational period should be considered partially LPL-deficient. Extreme instances of hyperlipidemia increase the risk of acute pancreatitis, and the effect of parturition on declining plasma lipid levels can be immediate and dramatic. Therefore, decisions regarding the timing and route of delivery with extreme gestational hyperlipidemia are critical and should be made carefully.

Vascular Lipid Accumulation, Lipoprotein Oxidation, and Macrophage Lipid Uptake in Hypercholesterolemic Zebrafish

Lipid accumulation in arteries induces vascular inflammation and atherosclerosis, the major cause of heart attack and stroke in humans. Extreme hyperlipidemia induced in mice and rabbits enables modeling many aspects of human atherosclerosis, but microscopic examination of plaques is possible only postmortem. Here we report that feeding adult zebrafish (Danio rerio) a high-cholesterol diet (HCD) resulted in hypercholesterolemia, remarkable lipoprotein oxidation, and fatty streak formation in the arteries. Feeding an HCD supplemented with a fluorescent cholesteryl ester to optically transparent fli1:EGFP zebrafish larvae in which endothelial cells express green fluorescent protein (GFP), and using confocal microscopy enabled monitoring vascular lipid accumulation and the endothelial cell layer disorganization and thickening in a live animal. The HCD feeding also increased leakage of a fluorescent dextran from the blood vessels. Administering ezetimibe significantly diminished the HCD-induced endothelial cell layer thickening and improved its barrier function. Feeding HCD to lyz:DsRed2 larvae in which macrophages and granulocytes express DsRed resulted in the accumulation of fluorescent myeloid cells in the vascular wall. Using a fluorogenic substrate for phospholipase A(2) (PLA(2)), we observed an increased vascular PLA(2) activity in live HCD-fed larvae compared to control larvae. Furthermore, by transplanting genetically modified murine cells into HCD-fed larvae, we demonstrated that toll-like receptor-4 was required for efficient in vivo lipid uptake by macrophages. These results suggest that the novel zebrafish model is suitable for studying temporal characteristics of certain inflammatory processes of early atherogenesis and the in vivo function of vascular cells.

Arachidonate 5-Lipoxygenase Variants in Atherosclerosis, Obesity, and Bone Traits

To the Editor: I write regarding publications by Mehrabian et al1,2 appearing in Circulation Research and a subsequent publication by Kuhn et al3 appearing in Arteriosclerosis, Thrombosis, and Vascular Biology . The key implication from the combination of these reports was that amino acid substitutions in arachidonate 5-lipoxygenase (ALOX5) could account for differences in susceptibility to atherosclerosis between mouse strains CAST/EiJ and C57BL/6J. The two putative amino acid substitutions reported by Mehrabian et al to be present in strain CAST/EiJ1 were at positions 645 and 646, which are conserved across human, mouse, rat, dog, cow, and chicken. Indeed, when Kuhn et al3 mutated either or both of these residues in the human …

Severe hyperlipidemia-associated pregnancy: prevention in subsequent pregnancy by diet.

Severe hyperlipidemia-associated pregnancy: prevention in subsequent pregnancy by diet.

Extreme Hyperlipidemia In Type I Diabetes Mellitus

The authors report their clinical experience with a 6-year-old girl with new-onset insulin-dependent diabetes mellitus (IDDM) who initially presented in severe diabetic ketoacidosis (DKA) with extreme hyperlipidemia.

Eruptive xanthomas in a child with the nephrotic syndrome

In a 4-year-old boy with steriod-resistant syndrome and extreme hyperlipidemia, an intense pruritic papular eruption developed on the trunk, buttocks, and extensor surface of the extremities. Findings from a skin biopsy specimen were consistent with an eruptive xanthoma. The patient was treated with gemfibrozil (Lopid), a low-fat diet, and antihistamines. Within 1 month pruritus diminished, the cutaneous lesions resolved, and serum lipid levels declined.

Plasma lipid peroxidation in hyperlipidemic chickens

Laying and genetically defective non-laying hens were evaluated for plasma lipid and plasma peroxidation levels. The non-layers developed extreme hyperlipidemia as well as greatly increased levels of lipid peroxidation. It was concluded that the concurrent presence of lipid peroxidation products must be considered when evaluating hyperlipidemic causes of atherosclerosis in the chicken.

Cholesterol fatty kidney: Morphological changes in the course of its development in rabbits

Kidneys from 90 rabbits were examined by light microscopy after an experiment designed to assess the possible relation between the cholesterol content of various tissues and two other factors: the serum cholesterol level and duration of hypercholesteremia. An additional eight rabbits were fed a 2% cholesterol diet for various periods up to 90 days. These kidney tissues were examined under electron microscope after aldehyde fixation with 0.2% digitonin. Digitonin-induced laminar and microtubular structures appeared in the capillary lumen and endothelia 5 hr after cholesterol feeding. Subsequently, similar structures appeared in the glomerular visceral epithelia and tubular epithelia. Fat vacuoles were usually not observed by light microscopy because of their small size and number. The interstitial cells in the medulla were sensitive to hypercholesteremia and were transformed into foam cells. As these grew in number, fatty streaks appeared and extended from the subcortical zone toward pyramidal papilla. The glomerular mesangial cells also took up cholesterol, but only after prolonged exposure to extreme hyperlipidemia, they formed glomerular micro-xanthomas.

Cholesterol contents of various tissues of chickens with exogenous or endogenous hypercholesteremia

Cholesterol contents of 16 different tissues were determined in 12 normal roosters, 12 roosters with diet-induced, exogenous hypercholesteremia, 10 actively laying hens with minimal endogenous hypercholesteremia, and 12 nonlaying hens with hereditable extreme hyperlipidemia. The tissue cholesterol contents of the normal roosters were strikingly similar to that of the corresponding tissues of the mammals except for a low cholesterol content of the brain in chickens. The hypercholesteremia in the roosters fed a 2% cholesterol diet for 2 months was associated with an increase of cholesterol content in all tissues except the brain, muscle, and adipose tissue. The actively laying hens, on the other hand, had a decreased cholesterol content in most tissues, despite the persistence of a minimal hypercholesteremia for 18 months and significant aortic cholesterol accumulation with mild atherosclerosis. The nonlaying hens developed extreme hypercholesteremia and severe atherosclerosis but only a moderately expanded cholesterol pool in most tissues. The results indicated a remarkable difference in tissue response to diet-induced exogenous hypercholesteremia and endogenous hyperlipidemia associated with laying activity in chickens and the propensity of their aortas to accumulate excessive cholesterol in the presence of either endogenous or exogenous hyperlipidemia.

Biophysics of the common fowl

Laying and genetically defective non-laying hens were evaluated for plasma lipid and plasma peroxidation levels. The non-layers developed extreme hyperlipidemia as well as greatly increased levels of lipid peroxidation. It was concluded that the concurrent presence of lipid peroxidation products must be considered when evaluating hyperlipidemic causes of atherosclerosis in the chicken.