Disturbances In Cholesterol Metabolism Research Articles

Cholesterol metabolism: physiological versus pathological aspects in intracerebral hemorrhage.

Cholesterol is an important component of plasma membranes and participates in many basic life functions, such as the maintenance of cell membrane stability, the synthesis of steroid hormones, and myelination. Cholesterol plays a key role in the establishment and maintenance of the central nervous system. The brain contains 20% of the whole body's cholesterol, 80% of which is located within myelin. A huge number of processes (e.g., the sterol regulatory element-binding protein pathway and liver X receptor pathway) participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis, intracellular transport, and efflux. Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences. Therefore, we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases. Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype, with high mortality and morbidity. Historical cholesterol levels are associated with the risk of intracerebral hemorrhage. Moreover, secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation, such as neuroinflammation, demyelination, and multiple types of programmed cell death. Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage. In this paper, we review normal cholesterol metabolism in the central nervous system, the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage, and the links between cholesterol metabolism and cell death. We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.

Mass Spectrometry Imaging of Cholesterol and Oxysterols.

Mass spectrometry imaging (MSI) is a new technique in the toolbox of the analytical biochemist. It allows the generation of a compound-specific image from a tissue slice where a measure of compound abundance is given pixel by pixel, usually displayed on a color scale. As mass spectra are recorded at each pixel, the data can be interrogated to generate images of multiple different compounds all in the same experiment. Mass spectrometry (MS) requires the ionization of analytes, but cholesterol and other neutral sterols tend to be poorly ionized by the techniques employed in most MSI experiments, so despite their high abundance in mammalian tissues, cholesterol is poorly represented in the MSI literature. In this chapter, we discuss some of the MSI studies where cholesterol has been imaged and introduce newer methods for its analysis by MSI. Disturbed cholesterol metabolism is linked to many disorders, and the potential of MSI to study cholesterol, its precursors, and its metabolites in animal models and from human biopsies will be discussed.

Cholesterol Metabolism Pathways Disturbances in Atherosclerosis—Analyses Using Stochastic Petri Net-Based Model

Atherosclerosis is a multifactorial disease that affects large arteries and causes much morbidity and mortality worldwide. Despite ongoing research for several decades, it is still a global health problem that cannot be stopped and cured completely. Furthermore, the development of this disease is contributed to by various processes, primarily disturbances in cholesterol metabolism, local low-grade inflammation, and oxidative stress, resulting in the formation of atherosclerotic plaques. In this work, a stochastic Petri net model was constructed and subsequently analyzed to examine the impact of these factors on the development and progression of atherosclerosis. The use of knockout- and simulation-based analysis allowed for a comprehensive investigation of the studied phenomena. Our research has demonstrated that while cholesterol is a contributing factor in atherosclerosis, blocking its impact alone is insufficient in halting the progression of this disorder. Inhibition of oxidative stress is also important when blocking the impact of phosphoprotein phosphatase inhibitor-1 (PPI-1), microsomal triglyceride transfer protein (MTTP), and 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR), as our model shows that this action reduces the number of foam cells underlying atherosclerosis. The results obtained further support the previous observations that the combined treatment is significantly effective in enhancing therapeutic efficacy against atherosclerosis.

PCSK9 involves in the high-fat diet-induced abnormal testicular function of male mice.

Impaired spermatogenesis resulting from disturbed cholesterol metabolism due to intake of high-fat diet (HFD) has been widely recognized, however, the role of preprotein invertase subtilin 9 (PCSK9), which is a negative regulator of cholesterol metabolism, has never been reported. This study aims to reveal the role of PCSK9 on spermatogenesis induced by HFD in mice. Long-term consumption of a high-fat diet (HFD) is an important factor that leads to impaired spermatogenesis exhibiting poor sperm quantity and quality. However, the mechanism of this is yet to be elucidated. Disrupted cholesterol homeostasis is one of many crucial pathological factors which could contribute to impaired spermatogenesis. As a negative regulator of cholesterol metabolism, preprotein invertase subtilin 9 (PCSK9) mediates low density lipoprotein receptor (LDLR) degradation to the lysosome, thereby reducing the expression of LDLR on the cell membrane and increasing serum low-density lipoprotein cholesterol level, resulting in lipid metabolism disorders. Here, we aim to study whether PCSK9 is a pathological factor for impaired spermatogenesis induced by HFD and the underlying mechanism. To meet the purpose of our study, we utilized wild-type C57BL/6 male mice and PCSK9 knockout mice with same background as experimental subjects and alirocumab, a PCSK9 inhibitor, was used for treatment. Results indicated that HFD induced higher PCSK9 expression in serum, liver, and testes, and serum PCSK9 is negatively correlated with spermatogenesis, while both PCSK9 inhibitor treatment and PCSK9 knockout methodologies ameliorated impaired lipid metabolism and spermatogenesis in mice fed a HFD. This could be due to the overexpression of PCSK9 induced by HFD leading to dyslipidemia, resulting in testicular lipotoxicity, thus activating the Bcl-2-Bax-Caspase3 apoptosis signaling pathway in testes, particularly in Leydig cells. Our study demonstrates that PCSK9 is an important pathological factor in the dysfunction of spermatogenesis in mice induced by HFD. This finding could provide innovative ideas for the diagnosis and treatment of male infertility.

Tissue-Specific Oxysterols as Predictors of Antidepressant (Escitalopram) Treatment Response in Patients With Major Depressive Disorder

BackgroundThere is growing evidence that disturbances in cholesterol metabolism may be involved in major depressive disorder (MDD). However, it is not known if cholesterol metabolites present in the brain and periphery can be used to diagnose and predict an MDD patient’s response to antidepressant treatment. MethodsA total of 176 subjects (85 patients with MDD and 91 healthy control subjects) were included in this study. The expression of peripheral and brain-specific oxysterols and related gene polymorphisms were investigated in all subjects. The severity of depression was measured using the 17-item Hamilton Depression Rating Scale, 16-item Quick Inventory of Depressive Symptoms–Self-Report, and Patient Health Questionnaire-9 for all patients with MDD before and after 12 weeks of antidepressant treatment. ResultsPatients with MDD expressed higher plasma levels of 24(S)-hydroxycholesterol (24OHC) (mainly secreted from the brain) compared with healthy control subjects, and the higher levels of 24OHC were associated with 24OHC synthetase (CYP46A1) gene polymorphisms. In patients with MDD, an improved response to the 12-week antidepressant treatment was associated with a reduction of both 24OHC and 27OHC (mainly secreted from the peripheral system) levels relative to baseline levels. Nonresponders exhibited increased levels of oxysterols at the end of treatment compared with baseline. The superior reduction in oxysterol levels correlated with better outcomes from the antidepressant treatment. ConclusionsThese data suggest a potential role for oxysterols as diagnostic and treatment response–related indicators for MDD.

Maternal exposure to polystyrene nanoparticles retarded fetal growth and triggered metabolic disorders of placenta and fetus in mice

Microplastics can enter the human body via direct body contact or the food chain, increasing the likelihood of adverse impacts on pregnancy and fetal development. We investigated the potential effects and modes of action of polystyrene nanoplastics (PS-NPs) in placenta and fetus using mice as a model species. Maternal PS-NP exposure (100 nm; 1 and 10 mg/L) via drinking water induced a significant decline in fetal weights at the higher exposure concentration. Abnormal morphologies of cells in the placenta and fetus were observed after exposure. For the placenta, transcriptomic analyses indicated that PS-NPs significantly disturbed cholesterol metabolism and complement and coagulation cascades pathways. Metabolomics showed appreciable metabolic disorders, particularly affecting sucrose and daidzein concentrations. For the fetal skeletal muscle, transcriptomics identified many significantly regulated genes, involving muscle tissue development, lipid metabolism, and skin formation. Transcriptomic analysis of the placenta and fetal skeletal muscle at the high PS-NP concentration showed that APOA4 and its transcriptional factors, facilitating cholesterol transportation, were significantly regulated in both tissues. Our study revealed that PS-NPs caused fetal growth restriction and significantly disturbed cholesterol metabolism in both placenta and fetus, offering new insights into the mechanisms underlying the placental and fetal effects in mice exposed to PS-NPs.

Control of Cholesterol Metabolism Using a Systems Approach.

Simple SummaryCholesterol is the main sterol in mammals that is essential for healthy cell functionining. It plays a key role in metabolic regulation and signaling, it is a precursor molecule of bile acids, oxysterols, and all steroid hormones. It also contributes to the structural makeup of the membranes. Its homeostasis is tightly controlled since it can harm the body if it is allowed to reach abnormal blood concentrations. One of the diseases associated with elevated cholesterol levels being the major cause of morbidities and mortalities worldwide, is atherosclerosis. In this study, we have developed a model of the cholesterol metabolism taking into account local inflammation and oxidative stress. The aim was to investigate the impact of the interplay of those processes and cholesterol metabolism disturbances on the atherosclerosis development and progression. We have also analyzed the effect of combining different classes of drugs targeting selected components of cholesterol metabolism.Cholesterol is an essential component of mammalian cells and is involved in many fundamental physiological processes; hence, its homeostasis in the body is tightly controlled, and any disturbance has serious consequences. Disruption of the cellular metabolism of cholesterol, accompanied by inflammation and oxidative stress, promotes the formation of atherosclerotic plaques and, consequently, is one of the leading causes of death in the Western world. Therefore, new drugs to regulate disturbed cholesterol metabolism are used and developed, which help to control cholesterol homeostasis but still do not entirely cure atherosclerosis. In this study, a Petri net-based model of human cholesterol metabolism affected by a local inflammation and oxidative stress, has been created and analyzed. The use of knockout of selected pathways allowed us to observe and study the effect of various combinations of commonly used drugs on atherosclerosis. The analysis results led to the conclusion that combination therapy, targeting multiple pathways, may be a fundamental concept in the development of more effective strategies for the treatment and prevention of atherosclerosis.

Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment.

Lifestyle- and genetically induced disorders related to disturbances in cholesterol metabolism have shown the detrimental impact of excessive cholesterol levels on a plethora of pathological processes such as inflammation. In this context, two-hydroxypropyl-β-cyclodextrin (CD) is increasingly considered as a novel pharmacological compound to decrease cellular cholesterol levels due to its ability to increase cholesterol solubility. However, recent findings have reported contra-indicating events after the use of CD questioning the clinical applicability of this compound. Given its potential as a therapeutic compound in metabolic inflammatory diseases, in this study, we evaluated the inflammatory effects of CD administration in the context of cholesterol-induced metabolic inflammation in vivo and in vitro. The inflammatory and cholesterol-depleting effects of CD were first investigated in low-density lipoprotein receptor knockout (Ldlr-/) mice that were transplanted with Npc1nih or Npc1wt bone marrow and were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 12 weeks, thereby creating an extreme model of lysosomal cholesterol-induced metabolic inflammation. In the final three weeks, these mice received daily injections of either control (saline) or CD subcutaneously. Subsequently, the inflammatory properties of CD were investigated in vitro in two macrophage cell lines and in murine bone marrow-derived macrophages (BMDMs). While CD administration improved cholesterol mobilization outside lysosomes in BMDMs, an overall pro-inflammatory profile was observed after CD treatment, evidenced by increased hepatic inflammation in vivo and a strong increase in cytokine release and inflammatory gene expression in vitro in murine BMDMs and macrophages cell lines. Nevertheless, this CD-induced pro-inflammatory profile was time-dependent, as short term exposure to CD did not result in a pro-inflammatory response in BMDM. While CD exerts desired cholesterol-depleting effects, its inflammatory effect is dependent on the exposure time. As such, using CD in the clinic, especially in a metabolic inflammatory context, should be closely monitored as it may lead to undesired, pro-inflammatory side effects.

The Role of Cholesterol Homeostasis in Diabetic Kidney Disease.

Considerable evidence has proved that disturbed cholesterol metabolism played a crucial role in diabetic kidney disease. Besides, massive cholesterol depositions were found in intrinsic renal cells of diabetic kidney disease patients and animal models, causing cytotoxicity and affecting renal function. Statins could alleviate cholesterol depositions, podocyte injury, and microalbuminuria of diabetic kidney disease. In this review, we summarized the process of disturbed cholesterol metabolism and discussed how it induced kidney dysfunction in diabetic kidney disease.

A Membrane-free Liver-Gut-on-Chip Platform for the Assessment on Dysregulated Mechanisms of Cholesterol and Bile Acid Metabolism Induced by PM2.5.

Fine particulate matter (PM2.5)-induced metabolic diseases have attracted a great deal of attention recently. However, the relevant metabolic mechanisms of PM2.5 in vivo have not yet been fully described due to the lack of reliable platforms. Herein, a membrane-free liver-gut-on-chip (L-GOC) platform was developed to investigate metabolism dysregulation induced by PM2.5. A multiple organ system with a liver-gut structure and two circulation paths (L-G and G-L circulation paths) was created, and then cells were exposed to PM2.5 on this platform. Secreted high-density lipoprotein (HDL) levels were detected, which demonstrates that this multiple organ system functioned with normal physiological metabolism at the organ level. Untargeted metabolomic analysis showed that there were 364 metabolites of LO2 cells dysregulated after exposure to PM2.5 at a concentration of 200 μg/mL. Moreover, cholesterol and bile acid metabolism were significantly dysregulated. Further immunofluorescence and ELISA assays confirmed that signal transduction pathways related to cholesterol metabolism (LCAT-CE, PON1-HDL, and SRB1-HDL metabolic pathways) and bile acid metabolism (CYP7A1-CA/CDCA/DCA metabolic pathways) were disturbed. These results indicate that PM2.5 primarily disturbed cholesterol metabolism of the liver and then disrupted bile acid metabolism of the liver (primary bile acid biosynthesis) and gut (secondary bile acid biosynthesis) via related metabolic pathways. These findings may partially explain the metabolic mechanisms of cells triggered by PM2.5 exposure.

NPY stimulates cholesterol synthesis acutely by activating the SREBP2-HMGCR pathway through the Y1 and Y5 receptors in murine hepatocytes

AimsThe development of non-alcoholic fatty liver disease (NAFLD) is partially attributed to disturbance in cholesterol metabolism and sympathetic overactivity. Excessive levels of the sympathetic neurotransmitter neuropeptide Y (NPY) positively correlated with both NAFLD and cholesterol accumulation. We wanted to determine, for the first time, whether NPY promotes cholesterol accumulation directly in hepatocytes and elucidate the underlying mechanism. Main methodsIn vivo, NPY was injected through the hepatic portal vein into SD rats. One hour later, serum and liver tissues were collected. In vitro, BRL-3A hepatocytes were treated with NPY, and with Y1, Y2, Y5, receptor antagonists as well as with extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) antagonist, respectively. Cholesterol content was measured by coupled enzyme method. Precursor sterol-regulatory element binding protein 2 (pSREBP2), mature SREBP2 (mSREBP2), HMG-CoA reductase (HMGCR), ERK1/2, pERK1/2, cAMP-dependent protein kinase (PKA), and pPKA protein expression levels were examined by western blotting. Key findingsIn rats, intraportal vein injection of NPY activates pSREBP2, mSREBP2, and HMGCR protein expression, and induces hepatic cholesterol accumulation. In BRL-3A cells, we observed that NPY increases cholesterogenic protein expression and cholesterol synthesis through Y1 and Y5 receptors. This effect is mediated by the activation of the ERK1/2 signaling pathway. SignificanceWe demonstrated, for the first time, that NPY can activate the cholesterogenic pathway and elucidated the underlying mechanism. Thus, NPY and NPY receptors might be new targets for the treatment of NAFLD and dyslipidemia.

Disturbances in Cholesterol Homeostasis and Non-alcoholic Fatty Liver Diseases.

Non-alcoholic fatty liver disease (NAFLD) is a major health problem associated with obesity and other features of the metabolic syndrome including insulin resistance and dyslipidemia. The accumulation of lipids in hepatocytes causes liver damage and triggers inflammation, fibrosis, and cirrhosis. Beside fatty acids and triglycerides, evidence showed an increased accumulation of free cholesterol in the liver with subsequent toxic effects contributing to liver damage. The maintenance of cholesterol homeostasis in the body requires a balance between several pathways responsible for cholesterol synthesis, transport and conversion into bile acids. Intestinal absorption is also one of the major determinants of cholesterol homeostasis. The nature of changes in cholesterol homeostasis associated with NAFLD has been a subject of extensive investigations. In this article, we will attempt to provide a brief overview of the current knowledge about the disturbances in cholesterol metabolism associated with NAFLD and discuss how certain molecular targets of these pathways could be exploited for the treatment of this multifactorial disease.

Obesity and related conditions and risk of inflammatory breast cancer: a nested case-control study.

Inflammatory breast cancer (IBC) is a rare, poorly understood and aggressive tumor. We extended prior findings linking high body mass index (BMI) to substantial increased IBC risk by examining BMI associations before and after adjustment for well-characterized comorbidities using medical record data for diabetes, insulin resistance, and disturbances of cholesterol metabolism in a general community healthcare setting. We identified 247 incident IBC cases diagnosed at Kaiser Permanente Northern California between 2005 and 2017 and 2470 controls matched 10:1 on birth year and geographic area and with ≥ 13months of continuous enrollment prior to diagnosis/index date. We assessed exposures from 6years up to one year prior to the diagnosis/index date, using logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Before adjustment for comorbidities, ORs (95% CIs) for BMI of 25-< 30, 30-< 35, and ≥ 35 compared to < 25kg/m2 were 1.5 (0.9-2.3), 2.0 (1.2-3.1), and 2.5 (1.4-4.4), respectively. After adjustment for pre-diabetes/diabetes, HDL-C and triglyceride levels, and dyslipidemia, corresponding ORs were 1.3 (0.8-2.1), 1.6 (0.9-2.9), and 1.9 (1.0-3.5). The OR for HDL-C levels < 50mg/dL compared to ≥ 65mg/dL was 2.0 (1.2-3.3) in the adjusted model. In a separate model the OR for a triglyceride/HDL-C ratio ≥ 2.50 compared to < 1.62 was 1.7 (1.1-2.8) after adjustment for BMI, pre-diabetes/diabetes, and dyslipidemia. Results did not differ significantly by estrogen receptor status. Obesity and measures of insulin resistance independently increased IBC risk as did obesity and low HDL-C levels. These findings, if confirmed, have implications for IBC prevention.

Corrigendum to “Ginger attenuates trimethylamine-N-oxide (TMAO)-exacerbated disturbance in cholesterol metabolism and vascular inflammation” [J. Funct. Foods 52 (2019) 25–33

Corrigendum to “Ginger attenuates trimethylamine-N-oxide (TMAO)-exacerbated disturbance in cholesterol metabolism and vascular inflammation” [J. Funct. Foods 52 (2019) 25–33

The Impact of Phytosterols on the Healthy and Diseased Brain.

The central nervous system (CNS) is the most cholesterol-rich organ in mammals. Cholesterol homeostasis is essential for proper brain functioning and dysregulation of cholesterol metabolism can lead to neurological problems. Multiple sclerosis (MS) and Alzheimer's disease (AD) are examples of neurological diseases that are characterized by a disturbed cholesterol metabolism. Phytosterols (PS) are plant-derived components that structurally and functionally resemble cholesterol. PS are known for their cholesterol-lowering properties. Due to their ability to reach the brain, researchers have started to investigate the physiological role of PS in the CNS. In this review, the metabolism and function of PS in the diseased and healthy CNS are discussed.

Ginger attenuates trimethylamine-N-oxide (TMAO)-exacerbated disturbance in cholesterol metabolism and vascular inflammation

Trimethylamine-N-oxide (TMAO) has recently been identified as an independent risk factor for atherosclerosis. The present study was to investigate the effects of ginger extract (GE) on plasma cholesterol and inflammation in TMAO-exacerbated hypercholesterolemic mice. Forty-five mice were assigned into five groups and fed a non-cholesterol diet, a high-cholesterol diet, or one of the three experimental high-cholesterol diets containing 1% GE, 0.2% TMAO, or 0.2% TMAO plus 1% GE for 12 weeks. Results showed that dietary TMAO increased plasma total cholesterol (TC). GE decreased plasma TC in both non-TMAO-fed and TMAO-fed mice, by up-regulating the expression of hepatic cholesterol 7α-hydroxylase (CYP7A1) and promoting fecal excretion of total acidic sterols. GE also lowered plasma levels of proinflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), and monocyte chemotactic protein 1 (MCP-1). It was concluded that GE could alleviate the TMAO-aggravated elevation in plasma TC and vascular inflammation in high cholesterol diet-fed mice.

Chromosomal aberrations and micronuclei structures after dermal exposure to polycyclic aromatic hydrocarbon and ultraviolet radiation

Lead exposure has been evidenced as a risk factor for Alzheimer’s disease (AD), mainly affecting the ageing. However, the early manifestation and mechanisms of AD-like pathology induced by lead exposure remains to be elucidated. Considering the fact that impaired cholesterol metabolism is associated with many neurodegenerative disorders including AD, in this study we focused on the role of cholesterol metabolism in lead induced premature AD-like pathology. We treated weaning rats with lead at different concentrations for 4 weeks. We found that developmental lead exposure increased amyloid-beta (Aβ) accumulation and amyloid plaque deposition in the cortex and hippocampus. Lead exposure increased amyloid precursor protein (APP) expression and activated the sterol regulatory element binding protein 2 (SREBP2)-beta secretase (BACE1) pathway. In addition, we found that lead exposure decreased cholesterol levels by upregulating the expression of liver X receptor-a (LXR-a) and ATP-binding cassette transporter protein family member A1 (ABCA1) and decreasing the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR) and low density lipoprotein receptor (LDL-R) in young rat brain tissues. Taken together, our data demonstrated that developmental lead exposure induced early manifestation of AD-like pathology and disturbed cholesterol metabolism in young rat brains.

Lead exposure induces Alzheimers’s disease (AD)-like pathology and disturbes cholesterol metabolism in the young rat brain

Lead exposure has been evidenced as a risk factor for Alzheimer’s disease (AD), mainly affecting the ageing. However, the early manifestation and mechanisms of AD-like pathology induced by lead exposure remains to be elucidated. Considering the fact that impaired cholesterol metabolism is associated with many neurodegenerative disorders including AD, in this study we focused on the role of cholesterol metabolism in lead induced premature AD-like pathology. We treated weaning rats with lead at different concentrations for 4 weeks. We found that developmental lead exposure increased amyloid-beta (Aβ) accumulation and amyloid plaque deposition in the cortex and hippocampus. Lead exposure increased amyloid precursor protein (APP) expression and activated the sterol regulatory element binding protein 2 (SREBP2)-beta secretase (BACE1) pathway. In addition, we found that lead exposure decreased cholesterol levels by upregulating the expression of liver X receptor-a (LXR-a) and ATP-binding cassette transporter protein family member A1 (ABCA1) and decreasing the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR) and low density lipoprotein receptor (LDL-R) in young rat brain tissues. Taken together, our data demonstrated that developmental lead exposure induced early manifestation of AD-like pathology and disturbed cholesterol metabolism in young rat brains.

Вплив різних поліфенолів на порушення обміну холестерину в умовах інсулінорезистентності

Вплив різних поліфенолів на порушення обміну холестерину в умовах інсулінорезистентності

Impact of Various Polyphenols on Disturbance of Cholesterol Metabolism under Insulin Resistance

The effects of therapeutic and prophylactic administration of quercetin, epigallocatechin gallate, and grape polyphenolic extract on changes in cholesterol metabolism in the rat blood serum under insulin resistance were studied. The development of atherogenic dislipoproteinemia has been revealed as evidenced by the accumulation of total cholesterol (2.12 times) due to the growth of the content of very low-density lipoprotein cholesterol (1.75 times), the decrease in the concentration of high-density lipoprotein cholesterol (2.6 times), and the increase in the atherogenicity index (8.8 times) in animals on a high-fructose diet. The use of all examined polyphenols in different ways normalized cholesterol metabolism. Grape polyphenolic extract has shown more pronounced protective properties, obviously, due to more diverse composition and, accordingly, mechanisms of insulin resistance correction.