Decreased Cholesterol Synthesis Research Articles

Dysregulation of cholesterol homeostasis is an early signal of β-cell proteotoxicity characteristic of type 2 diabetes.

Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic β-cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in β-cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed and cosecreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in β-cells in T2D and in β-cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and prediabetic 9- to 10-wk-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. Here, we investigated islets from hIAPP transgenic mice at an earlier age (6 wk) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. We identified early suppression of cholesterol synthesis and trafficking along with aberrant intra-β-cell cholesterol and lipid deposits and impaired cholesterol trafficking to cell membranes. These findings align with comparable lipid deposits present in β-cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis.NEW & NOTEWORTHY β-Cell failure in type 2 diabetes (T2D) is characterized by β-cell misfolded protein stress due to the formation of toxic oligomers of islet amyloid polypeptide (IAPP). Most transcriptional changes in islets in T2D are pro-survival adaptations consistent with the slow progression of β-cell loss. In the present study, investigation of the islet transcriptional signatures in a mouse model of T2D expressing human IAPP revealed decreased cholesterol synthesis and trafficking as a plausible early mediator of IAPP toxicity.

Silencing MUC1 to regulate intracellular lipid metabolism: Overcoming sunitinib resistance and inhibiting metastasis in renal cell carcinoma

Renal cell carcinoma (RCC) has been extensively studied and is a paradigmatic example of a malignancy distinguished by metabolic reprogramming. Reprogramming lipid metabolism is crucial for determining the response and resistance to chemotherapy. To overcome this, we developed a modified nanomicelle delivery system comprising polyethyleneimine (PEI) as a positive charge donor and ibuprofen as the hydrophobic end. The overall system, denoted as SPPI, is PEGylated, conjugated with sialic acid, and plays a targeting role. This system successfully delivered siRNA to cancer cells by overcoming systemic and cellular barriers. The resulting conjugates form uniform, spherical nanomicelles (37.8 ± 0.9 nm; 25.5 ± 1.4 mV) with targeting ability, stability, efficient delivery, and low toxicity. The complicated and indirect way cholesterol affects ATP-binding cassette transporters was investigated. Administering SPPI/siMUC1 resulted in significant suppression of MUC1 expression and a 3.25-fold decrease in cholesterol synthesis compared to the control, and it subsequently reversed resistance to sunitinib by modulating P-GP, ABCG2, and MRP1 activities. Importantly, SPPI/siMUC1 nanomicelles demonstrated outstanding growth inhibition (72.2 %) of sunitinib-resistant 786-O cell xenografts and remarkable inhibitory effects on tumor metastasis (45.0 %) without observable systemic toxicity according to tissue analysis and weight change evaluation. The efficacy and safety of SPPI/siMUC1 in the treatment of ccRCC were demonstrated, especially after drug resistance develops. Thus, this study introduces a novel strategy for addressing drug resistance in metabolically active cancers by targeting the lipid metabolism pathway.

Oleanolic acid inhibits cholesterol synthesis by suppressing the expression and enzymatic activity of HMGCR

ABSTRACT This study investigated the impact of Oleanolic Acid (OA) on cholesterol metabolism and. MTT assays demonstrated that OA had no cytotoxic effects on HepG2 cells at concentrations below 20 μM. Subsequent experiments focused on 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), a key enzyme in cholesterol biosynthesis. OA significantly reduced HMGCR protein expression without affecting other enzymes. Further investigations revealed that OA reduced the protein and mRNA expression of HMGCR and its upstream regulator Sterol regulatory element binding protein-2 (SREBP-2) in HepG2 cells. OA activated Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK), enhancing HMGCR phosphorylation and inhibiting its activity. Molecular docking experiments suggested that OA could suppress HMGCR enzymatic activity through hydrophobic interactions, reducing catalytic efficiency. Overall, OA downregulated HMGCR expression and activity, leading to decreased cholesterol synthesis. These findings highlight OA’s regulatory role in cholesterol metabolism and its potential for improving atherosclerosis (AS), supporting its application in functional food development.

Mevalonate pathway and male reproductive aging.

Male fertility declines with age. The mevalonate pathway, through which cholesterol and nonsteroidal isoprenoids are synthesized, plays key role in metabolic processes and is an essential pathway for cholesterol production and protein prenylation. Male reproductive aging is accompanied by dramatic changes in the metabolic microenvironment of the testis. Since the mevalonate pathway has an important role in spermatogenesis, we attempted to explore the association between male reproductive aging and the mevalonate pathway to explain the mechanism of male reproductive aging. Alterations in the mevalonate pathway may affect male reproductive aging by decreasing cholesterol synthesis and altering testis protein prenylation. Decreased cholesterol levels affect cholesterol modification, testosterone production, and remodeling of germ cell membranes. Aging-related metabolic disorders also affect the metabolic coupling between somatic cells and spermatogenic cells, leading to male fertility decline. Therefore, we hypothesized that alterations in the mevalonate pathway represent one of the metabolic causes of reproductive aging.

Fresh and Browned Lotus Root Extracts Promote Cholesterol Metabolism in FFA-Induced HepG2 Cells through Different Pathways.

Browning of fresh-cut plants is mainly attributed to the enzymatic browning of phenolic compounds induced by polyphenol oxidase (PPO), producing browning products such as anthraquinones, flavanol oxides, and glycosides, which are usually considered to be non-toxic. Could browning bring any benefits on behalf of their bioactivity? Our previous study found that browned lotus root extracts (BLREs) could reduce the cholesterol level in obese mice as fresh lotus root extracts (FLREs) did. This study aimed to compare the mechanisms of FLRE and BLRE on cholesterol metabolism and verify whether the main component's monomer regulates cholesterol metabolism like the extracts do through in vitro experiments. Extracts and monomeric compounds are applied to HepG2 cells induced by free fatty acids (FFA). Extracellular total cholesterol (TC) and triglyceride (TG) levels were also detected. In addition, RT-PCR and Western blot were used to observe cholesterol metabolism-related gene and protein expression. The in vitro results showed that BLRE and FLRE could reduce TC and TG levels in HepG2 cells. In addition, BLRE suppressed the synthesis of cholesterol. Meanwhile, FLRE promoted the synthesis of bile acid (BA) as well as the clearance and efflux of cholesterol. Furthermore, the main monomers of BLRE also decreased cholesterol synthesis, which is the same as BLRE. In addition, the main monomers of FLRE promoted the synthesis of BAs, similar to FLRE. BLRE and FLRE promote cholesterol metabolism by different pathways.

The IDI1/SREBP2 axis drives intrahepatic cholestasis and is a treatment target of San-Huang-Cai-Zhu formula identified by sequencing and experiments.

San-Huang-Chai-Zhu formula (SHCZF), originates from Da-Huang-Xiao-Shi decoction (DHXSD) for the treatment of jaundice as recorded in the Chinese traditional Chinese medicine book Jin Gui Yao Lue. In the clinic, SHCZF has been used to treat cholestasis-related liver disease by improving intrahepatic cholestasis, but the treatment mechanism has not been elucidated. In this study, 24 Sprague-Dawley (SD) rats were randomly assigned to the normal, acute intrahepatic cholestasis (AIC), SHCZF, and ursodeoxycholic acid (UDCA) groups. In addition, 36 SD rats were divided into dynamic groups, namely, normal 24h, AIC 24h, normal 48h, AIC 48h, normal 72h, and AIC 72h groups. Alpha-naphthylisothiocyanate (ANIT) was used to induce an AIC rat model. Serum biochemical indices and hepatic pathology were detected. Part of the hepatic tissues was used for sequencing, and others were used for subsequent experiments. Sequencing data combined with bioinformatics analysis were used to screen target genes and identify the mechanisms of SHCZF in treating AIC rats. Quantitative real-time PCR (qRT-PCR) and Western blotting (WB) were used to detect the RNA/Protein expression levels of screened genes. Rats in the dynamic group were used to determine the sequence of cholestasis and liver injury. High-performance liquid chromatography (HPLC) was used to determine the representative bioingredients of SHCZF. Sequencing and bioinformatics analysis suggested that IDI1 and SREBP2 are hub target genes of SHCZF to ameliorate ANTI-induced intrahepatic cholestasis in rats. The treatment mechanism is associated with the regulation of lipoprotein receptor (LDLr) to reduce cholesterol intake and 3-Hydroxy-3-Methylglutaryl-CoA reductase (HMGCR), and 3-Hydroxy-3-Methylglutaryl-CoA synthase 1 (HMGCS1) to decrease cholesterol synthesis. Animal experiments showed that SHCZF significantly reduced the expression levels of the above genes and proinflammatory cytokine lipocalin 2 (LCN2), inflammatory cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), thereby improving intrahepatic cholestasis and inflammation and liver injury.

Resveratrol Modulates the Redox Response and Bile Acid Metabolism to Maintain the Cholesterol Homeostasis in Fish Megalobrama amblycephala Offered a High-Carbohydrate Diet.

This study aimed to characterize the effects of resveratrol on the redox balance, cholesterol homeostasis and bile acid metabolism of Megalobrama amblycephala offered a high-carbohydrate diet. Fish (35.0 ± 0.15 g) were fed four diets including one control diet (32% nitrogen-free extract), one high-carbohydrate diet (45% nitrogen-free extract, HC), and the HC diet supplemented with different levels (0.04%, HCR1; 0.08%, HCR2) of resveratrol for 12 weeks. The HC diet-induced redox imbalance is characterized by increased MDA content and decreased T-SOD and CAT activities in the liver. Resveratrol attenuated this by up-regulating the transcription of Cu/Zn-sod, and increasing the activities of T-SOD, CAT, and GPX. The HC diet enhanced the cholesterol synthesis, but decreased the bile acid synthesis via up-regulating both hmgcr and acat2, and down-regulating cyp7a1, thus resulting in excessive cholesterol accumulation. Resveratrol supplement decreased cholesterol synthesis, and increased cholesterol uptake in the liver by down-regulating both hmgcr and acat2, and up-regulating ldlr. It also increased bile acid synthesis and biliary excretion by up-regulating cyp7a1, and down-regulating mrp2, oatp1, and oatp4 in the hindgut, thereby decreasing cholesterol accumulation. In conclusion, resveratrol improves the cholesterol homeostasis of Megalobrama amblycephala fed a high-carbohydrate diet by modulating the redox response and bile acid metabolism.

Methionine regulates self-renewal, pluripotency, and cell death of GIC through cholesterol—rRNA axis

BackgroundGlioma-initiating cells (GICs) are the source of glioma cells that can self-renew, have pluripotency, and are treatment-resistant, so are the starting point for relapse and eventual death despite multimodality therapy. L-[methyl-11C] methionine PET has observed high accumulation at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism. MethodsWe cultured cells in methionine-deprived culture medium for comprehensive analysis. Based on the obtained results, the possible target molecules were chemically inhibited and the respective markers were analyzed.ResultsMethionine depletion markedly decreased proliferation and increased cell death of GICs. Decreased S-adenosyl-methionine, which is synthesized intracellularly by catalyzed by methionine adenosyltransferase using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotency of stem cells, (iii) decreased expression of the core-genes and pluripotent markers of stem cells including FOXM1, SOX2, SOX4, PROM1, and OLIG2, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2, and (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, small nucleolar RNA guiding the pseudouridylation of 28S rRNA, which is essential for translation. In addition, inhibition of cholesterol synthesis with statin resulted in a phenotype similar to that of methionine depletion and decreases in stem cell markers and small nucleolar RNA ACA43. Moreover, suppression of FOXM1 decreased stem cell markers such as SOX4 and PROM1. The gene expression profile for cholesterol production was obtained from the Ivy Glioblastoma Atlas Project database and compared between tumor cells with relatively low methionine levels in areas of pseudopalisading arrangement around necrosis and tumor cells in the infiltrating region, showing that cells in the infiltrating region have higher capacity to produce cholesterol.ConclusionsMethionine metabolism is closely related with self-renewal, pluripotency, and cell death in GICs through modification of cholesterol biosynthesis, especially in the SREBF2-FOXM1 and ACA43 axis with modification of rRNA.

PSUN66 Statin Intake as a Cause of Decreased Steroid Hormone Secretion

Abstract Materials and methods The study enrolled 2 men aged 58 years (history of acute cerebral circulation disorder at 47 and 57 years) and 64 years (history of acute myocardial infarction at 62 years), who complained of shortness of breath, daytime sleepiness, decreased libido, weakened erections, increased blood pressure. Both patients had been taking atorvastatin 10 mg for more than three months. We used high-performance liquid chromatography (HPLC) to determine steroid hormones in saliva: Agilent 1200 chromatograph, AB Sciex 3200 MD mass spectrometer (Sciex, USA). Saliva was collected in a Salivette container. A significant decrease in pregnenolone levels of 440.0 pg/ml and 300 pg/ml, respectively, was detected in the saliva analyses). The norm for pregnenolone was 575-665 pg/ml. Conclusion Statins lead to decreased pregnenolone secretion, most likely due to inhibition of HMG-CoA reductase, a key enzyme that converts 3-hydroxy-3-methyl glutaryl-CoA to mevalonate, a cholesterol precursor. The decrease in cholesterol synthesis leads to a decrease in pregnenolone and a decrease in steroid hormone secretion, both in the adrenal glands and gonads, which clinically manifests as hypogonadism and adrenal fatigue. All patients taking statins should have their salivary steroid profile evaluated. If statins cannot be withdrawn, hormone replacement therapy with sex hormones is necessary. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Intratracheal exposure to polyhexamethylene guanidine phosphate disrupts coordinate regulation of FXR-SHP-mediated cholesterol and bile acid homeostasis in mouse liver

A public health crisis in the form of a significant incidence of fatal pulmonary disease caused by repeated use of humidifier disinfectants containing polyhexamethylene guanidine phosphate (PHMG) recently arose in Korea. Although the mechanisms of pulmonary fibrosis following respiratory exposure to PHMG are well described, distant-organ effect has not been reported. In this study, we investigated whether intratracheal administration of PHMG affects liver pathophysiology and metabolism. Our PHMG mouse model showed a significant decrease in liver cholesterol level. An mRNA-seq analysis of liver samples revealed an alteration in the gene expression associated with cholesterol biosynthesis and metabolism to bile acids. The expression of genes involved in cholesterol synthesis was decreased in a real-time PCR analysis. To our surprise, we found that the coordinate regulation of cholesterol and bile acid homeostasis was completely disrupted. Despite the decreased cholesterol synthesis and low bile acid levels, the farnesoid X receptor/small heterodimer partner pathway, which controls negative feedback of bile acid synthesis, was activated in PHMG mice. As a consequence, gene expression of Cyp7a1 and Cyp7b1, the rate-limiting enzymes of the classical and alternative pathways of bile acid synthesis, was significantly downregulated. Notably, the changes in gene expression were corroborated by the hepatic concentrations of the bile acids. These results suggest that respiratory exposure to PHMG could cause cholestatic liver injury by disrupting the physiological regulation of hepatic cholesterol and bile acid homeostasis.

Effects of Diet-Induced Weight Loss on Plasma Markers for Cholesterol Absorption and Synthesis: Secondary Analysis of a Randomized Trial in Abdominally Obese Men.

Cross-sectional studies have shown that obesity is associated with lower intestinal cholesterol absorption and higher endogenous cholesterol synthesis. These metabolic characteristics have also been observed in patients with type 2 diabetes, metabolic syndrome, steatosis or cholestasis. The number of intervention studies evaluating the effect of weight loss on these metabolic characteristics is, however, limited, while the role of the different fat compartments has not been studied into detail. In a randomized trial, abdominally obese men (N = 54) followed a 6-week very low caloric (VLCD) diet, followed by a 2 week weight-maintenance period. Non-cholesterol sterols were measured at baseline and after 8 weeks, and compared to levels in lean participants (N = 25). After weight loss, total cholesterol (TC)-standardized cholestanol levels increased by 0.18 µmol/mmol (p < 0.001), while those of campesterol and lathosterol decreased by 0.25 µmol/mmol (p < 0.05) and 0.39 µmol/mmol (p < 0.001), respectively. Moreover, after weight loss, TC-standardized lathosterol and cholestanol levels were comparable to those of lean men. Increases in TC-standardized cholestanol after weight loss were significantly associated with changes in waist circumference (p < 0.01), weight (p < 0.001), BMI (p < 0.001) and visceral fat (p < 0.01), but not with subcutaneous and intrahepatic lipids. In addition, cross-sectional analysis showed that visceral fat fully mediated the association between BMI and TC-standardized cholestanol levels. Intrahepatic lipid content was a partial mediator for the association between BMI and TC-standardized lathosterol levels. In conclusion, diet-induced weight loss decreased cholesterol synthesis and increased cholesterol absorption. The increase in TC-standardized cholestanol levels was not only related to weight loss, but also to a decrease in visceral fat volume. Whether these metabolic changes ameliorate other metabolic risk factors needs further study.

CBMS-10 Methionine metabolism closely related with self-renew, pluripotency and cell death in GICs through modification of cholesterol biosynthesis and ribosomal RNA

Glioma initiating cells (GICs) are the source of glioma cells that have the ability to self-renew and pluripotency, which are treatment-resistant, starting point for relapse and eventual death despite multimodality therapy. Since high accumulation is observed in 11cMet-PET at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism. We cultured cells in methionine-deprived culture medium and performed a comprehensive analysis, and found that methionine depletion markedly decreased proliferation and increasing cell death of GICs. Decreased SAM, which is synthesized intracellularly catalyzed by methionine adenosyltransferase (MAT) using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotentcy of stem cells, (iii) decreased expression of the core-genes and pluripotent marker of stem cells including FOXM1, SOX2, SOX4, PROM1 and OLIG2, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2 (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, snoRNA guiding the pseudouridylation of 28S ribosomal RNA, which has crucial role for translation. In addition, inhibition of cholesterol synthesis with statin resulted in a phenotype similar to that of methionine removal and a decrease in stem cell markers and snoRNA ACA43. Moreover, suppression of FOXM1 decreased stem cell markers such as SOX4 and PROM1. The gene expression profile for cholesterol production was obtained from the Ivy Glioblastoma Atlas Project (IVYGAP) database and compared between tumour cells with relatively low methionine levels in area of pseudopalisading arrangement around necrosis and tumour cells in the infiltrating region, showing that cells cells in the infiltrating region have a higher capacity to produce cholesterol. Taken together, methionine metabolism closely related with self-renew, pluripotency and cell death in GICs through modification of cholesterol biosynthesis: especially SREBF2-FOXM1 and ACA43 axis with modification of ribosomal RNA.

TAMI-62. METHIONINE METABOLISM CLOSELY RELATED WITH SELF-RENEW, PLURIPOTENCY AND CELL DEATH IN GICS THROUGH MODIFICATION OF CHOLESTEROL BIOSYNTHESIS, RIBOSOMAL RNA AND AUTOPHAGY

Abstract Glioma initiating cells (GICs) are the source of glioma cells that have the ability to self-renew and pluripotency, which are treatment-resistant, starting point for relapse and eventual death despite multimodality therapy. Since high accumulation is observed in 11cMet-PET at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism. We cultured cells in methionine-deprived culture medium and performed a comprehensive analysis, and found that methionine depletion markedly decreased proliferation and increasing cell death of GICs. Decreased SAM, which is synthesized intracellularly catalyzed by methionine adenosyltransferase (MAT) using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotentcy of stem cells, (iii) decreased expression of the core-genes and pluripotent marker of stem cells, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2 and FOXM1, (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, snoRNA guiding the pseudouridylation of 28S ribosomal RNA, which has crucial role for translation and (vi) possible connection between methionine metabolism and pluripotency, protein synthesis through cholesterol metabolism: SREBF2-FOXM1 and ACA43 axis, respectively. (vii) Disruption of autophagy by insufficient formation of macroautophagosomes. In conclusion, methionine metabolism closely related with self-renew, pluripotency and cell death in GICs through modification of cholesterol biosynthesis, ribosomal RNA and autophagy.

Key chemical composition of walnut (Juglans regia. L) Oils generated with different processing methods and their cholesterol-lowering effects in HepG2 cells

We systematically evaluated fatty acids and triacylglycerol composition, as well as tocopherol, phytosterol, and phenolics, in walnut oil and compared the cholesterol-lowering effects of oil processed with different methods (cold pressing, roast-pressing, hexane extraction, subcritical butane extraction, and supercritical CO2 extraction). The different methods did not affect the lipid composition of walnut oil. The tocopherol (41.11 mg/100 g) and total phenolic content (TPC, 4.26 mg/100 g) of roast-pressed walnut oil and the phytosterol contents of subcritical butane-extracted walnut oil (106.51 mg/100 g) were higher than those of other tested oils. Walnut oil significantly decreased cholesterol synthesis by downregulating the expression of HMGCR, SREBP-2, and CYP51 genes, and increased cholesterol efflux by upregulating the expression of ABCG1, thus significantly reducing total cholesterol and triacylglycerol. Phytosterols and TPC in walnut oil were responsible for lowering cholesterol; the optimal concentration of phytosterols was 10 μg/mL, and that of TPC was 12.5 × 10−3 μg/mL. Through process optimization, a new processing method for walnut oil based on biological evaluation was preliminarily established.

A REVIEW ON ENZYME INHIBITORS

Enzymes play very important role in living organism as biocatalyst. They play vital role like secretion, metabolism, digestion, DNA functions, reproduction, conversation of molecules and many other functions of body. By inhibiting specific enzymes, we can cure numerous pathological conditions in humans like inhibiting HMG CoA reductase, we can decrease cholesterol synthesis which is very useful in atherosclerosis and also use for heart diseases. ACE inhibitors can reduce concentration of Angiotensin II and use to reduce blood pressure. Many of them use as pesticides and herbicides in agriculture field. The history says enzyme inhibitors are use as arrow poison and use to kill animals by developing paralysis in them. Using a digital technology scientist identified number of enzymes and their functions as well as their 3D structure. We can easily design their inhibitors and use as medicine to treat pathological conditions. So, enzyme inhibitors became first choice for medicinal chemist and scientist as a target and play extremely important role in future as medicinal compounds and became a safe option compared to other available options.

Sterol sulfate alleviates atherosclerosis via mediating hepatic cholesterol metabolism in ApoE-/- mice.

Compared with terrestrial organisms, the sterols in sea cucumber exhibit a sulfate group at the C-3 position. Our previous study demonstrated that dietary sterol sulfate was superior to phytosterol in alleviating metabolic syndrome by ameliorating inflammation and mediating cholesterol metabolism in high-fat-high-fructose diet mice, which indicated its potential anti-atherosclerosis bioactivity. In the present study, administration with sea cucumber-derived sterol sulfate (SCS) significantly decreased the cholesterol level in oleic acid/palmitic acid-treated HepG2 cells, while no significant changes were observed in the triacylglycerol level. RNA-seq analysis showed that the metabolic changes were mostly attributed to the steroid biosynthesis pathway. ApoE-/- mice were used as an atherosclerosis model to further investigate the regulation of SCS on cholesterol metabolism. The results showed that SCS supplementation dramatically reduced atherosclerotic lesions by 45% and serum low-density lipoprotein cholesterol levels by 59% compared with the model group. Dietary SCS inhibited hepatic cholesterol synthesis via downregulating SREBP-2 and HMGCR. Meanwhile, SCS administration increased cholesterol uptake via enhancing the expression of Vldlr and Ldlr. Noticeably, SCS supplementation altered bile acid profiles in the liver, serum, gallbladder and feces, which might cause the activation of FXR in the liver. These findings provided new evidence about the high bioactivity of sterols with the sulfate group on atherosclerosis.

INDIVIDUAL CORRECTION OF THE TREATMENT OF PATIENTS WITH HEPATOSPLENOMEGALY SYNDROME, TAKING INTO ACCOUNT THE PARAMETERS OF LIPID AND PROTEIN METABOLISM

Summary. Purpose: to identify the features of lipid metabolism in patients with hepatosplenomegaly syndrome (HSS) of various origins to develop an individualized approach to the treatment of patients with this pathology.&#x0D; Materials and methods: blood serum of 73 patients with HSS on the background of liver cirrhosis complicated by portal hypertension, divided into 3 groups 1) with the etiological factor of hepatitis viruses HCV / HBV, 2) with autoimmune hepatitis with the etiological factor of the herpes group viruses CMV / VEB, 3) against the background of liver hepatosis and fermentopathies.&#x0D; Results and its discussion. In patients with HSS, multidirectional changes in the synthesis of lipid fractions were observed, also associated with impaired protein metabolism, namely:&#x0D; - with HSS against the background of viral hepatitis B and C, hypocholesterolemia and hypobetacholesterolemia were observed due to a decrease in cholesterol synthesis in hepatocytes; a decrease in the concentration of HDL is also associated with a violation of the process of cholesterol esterification due to a deficiency of the enzyme lecithin cholesterol acyltransferase, and an increase in the concentration of LDL is associated with a deficiency of the enzyme lipoprotein lipase in viral damage to hepatocytes.&#x0D; - with HSS against the background of autoimmune hepatitis, no significant changes were observed in the synthesis of lipid fractions;&#x0D; - in hepatosis (fermentopathies), type 5 hyperlipidemia with hypercholesterolemia and hypotriglyceridemia was found, which are a consequence of impaired formation and excretion of lipids from the liver, probably as a result of a decrease in the synthesis of apoproteins and indicate the accumulation of fat in hepatocytes and the formation of hepatosis.&#x0D; Conclusion:&#x0D; &#x0D; Surgical or endovascular treatment of HSS against the background of liver cirrhosis or hepatosis needs to be supplemented with individualized metabolic drug therapy, including lipid-lowering therapy.&#x0D; When detecting hypocholesterolemia and hypobetacholesterolemia in the first group, lipid-lowering therapy is not indicated, whereas if type 5 hyperlipidemia with hypercholesterolemia and hypotriglyceridemia is detected in the group of patients with fatty hepatosis, lipid-lowering therapy is necessary.&#x0D;

SUN-751 RORγ Is a Master Regulator of Tumor Lipid Metabolism

Lipid and cholesterol metabolism reprogramming is strongly linked to tumorigenesis and therapeutic resistance. Our recent genetic disruptions via CRISPR KO and gene silencing and pharmacological inhibition clearly demonstrated that nuclear receptor RORγ plays a crucial role in control of lipid and cholesterol biosynthesis gene programs specifically in certain types and subtypes of cancer cells and tumors. Indeed, its antagonists display potent tumor inhibitions in patient-derived xenografts (PDX) and in immune-intact tumor models. Interestingly, RORγ inhibition resulted in decreased cholesterol synthesis rate specifically in tumors without significant impact to the host animal cholesterol homeostasis. Our ChIP-seq demonstrated that in a subtype of breast cancer RORγ cistrome is largely overlapping with that of SREBP2, a well-established master regulator of lipid and cholesterol biosynthesis. Our further analyses found that RORγ functions dominantly over that of SREBP2 via its association with SREBP2 and facilitation of its genome-wide recruitment and histone H3K27 acetylation. Inhibition of RORγ completely negates the negative feedback activation of the cholesterol program induced by cholesterol-lowering drug statins and mediated by SREBP2. Treatment of animals with the antagonists in combination with statins showed a highly synergistic anti-tumor effects. Together, our study uncovers RORγ as a novel master regulator of lipid and cholesterol metabolism operating selectively in subtypes of cancer.

Running Head: Heat Affects Cholesterol and Bile Acid Alterations in Cholesterol and Bile Acids Metabolism in Large White Pigs during Short-Term Heat Exposure.

Heat stress influences lipid metabolism independently of nutrient intake. It is not well understood how cholesterol and bile acid (BA) metabolism are affected by heat stress. To investigate the alterations of cholesterol and bile acids when pigs are exposed to short term heat stress, 24 Large White pigs (63.2 ± 9.5 kg body weight, BW) were distributed into one of three environmental treatments: control conditions (CON, 23 °C with ad libitum intake; n = 8), heat stress conditions (HS, 33 °C with ad libitum intake; n = 8), or pair-fed conditions (PF, 23 °C with the same amount to the feed consumed by the HS; n = 8) for three days. Compared with CON pigs, HS pigs reduced the average daily feed intake and average daily gain by 55% and 124%, respectively, and significantly increased rectal temperatures by 0.9 °C and respiration rates more than three-fold. The serum total cholesterol (TC), low-density lipoprotein-cholesterol, and triglycerides (TG) increased (p < 0.05), while hepatic TC, TG, and mRNA of 3-hydroxy-3-methylglutaryl-CoA reductase were reduced on day 3. Furthermore, liver taurine-conjugated BAs (TCBAs), including taurolithocholic acid, taurochenodeoxycholic acid (TCDCA), tauroursodeoxycholic acid, taurohyodeoxycholic acid, and taurocholic acid were elevated in HS pigs compared to CON and PF pigs (p < 0.05), and the level of chenodeoxycholic acid was more significant in the PF group than in the CON and HS groups. The concentration of ursodeoxycholic acid in the serum was higher in HS pigs than CON and PF pigs (p < 0.05), and TCDCA was increased in HS pigs compared with PF pigs (p < 0.05). Altogether, short-term HS reduced hepatic cholesterol levels by decreasing cholesterol synthesis, promoting cholesterol to TCBAs conversion, and cholesterol release to serum in growing pigs. This independently reduced feed intake might serve as a mechanism to protect cells from damage during the early period.

Stroke-prone spontaneously hypertensive rats have reduced hydroxysteroid 17-β dehydrogenase 7 levels for low cholesterol biosynthesis.

Reduced serum cholesterol content was recently reported to be one of the factors responsible for cerebral haemorrhage. Stroke-prone spontaneously hypertensive rats (SHRSP) are known to have lower serum cholesterol content than normotensive Wistar-Kyoto rats (WKY). We previously reported that lower levels of mevalonate pyrophosphate decarboxylase (MPD) and squalene epoxidase (SQE), which are associated with cholesterol biosynthesis in the liver, are involved in the low serum cholesterol content in SHRSP. Here, we investigate the levels of sterol 14-demethylase (CYP51), methylsterol monooxygenase (SC4MOL), and hydroxysteroid 17-β dehydrogenase 7 (HSD17B7), which contribute to the cholesterol synthesis pathway in the conversion of lanosterol to zymosterol, in SHRSP and WKY. The HSD17B7 mRNA levels in the liver of SHRSP were markedly lower than those in WKY, whereas no significant differences were observed in CYP51 and SC4MOL levels in the two types of rats. The relative levels of protein, heteronuclear RNA, and mRNA of HSD17B7 were also significantly lower in SHRSP than in WKY. The degradation rates of HSD17B7 were the same in SHRSP and WKY. The protein levels of HSD17B7 were not significantly reduced in tissues other than the liver, including the brain, lung, heart, spleen, kidney, and testis, in SHRSP. Moreover, HSD17B7 activity was significantly lower in SHRSP than in WKY. Thus, our results indicated that low protein levels and activity of HSD17B7 are responsible for the reduced cholesterol content in SHRSP, indicating that HSD17B7, along with MPD and SQE, is involved in the decreased cholesterol synthesis in the liver of SHRSP.