Regulation Of Cholesterol Metabolism Research Articles

Osteocytes/Osteoblasts Produce SAA3 to Regulate Hepatic Metabolism of Cholesterol.

Hypercholesterolaemia is a systemic metabolic disease, but the role of organs other than liver in cholesterol metabolism is unappreciated. The phenotypic characterization of the Tsc1Dmp1 mice reveal that genetic depletion of tuberous sclerosis complex 1 (TSC1) in osteocytes/osteoblasts (Dmp1-Cre) triggers progressive increase in serum cholesterol level. The resulting cholesterol metabolic dysregulation is shown to be associated with upregulation and elevation of serum amyloid A3 (SAA3), a lipid metabolism related factor, in the bone and serum respectively. SAA3, elicited from the bone, bound to toll-like receptor 4 (TLR4) on hepatocytes to phosphorylate c-Jun, and caused impeded conversion of cholesterol to bile acids via suppression on cholesterol 7 α-hydroxylase (Cyp7a1) expression. Ablation of Saa3 in Tsc1Dmp1 mice prevented the CYP7A1 reduction in liver and cholesterol elevation in serum. These results expand the understanding of bone function and hepatic regulation of cholesterol metabolism and uncover a potential therapeutic use of pharmacological modulation of SAA3 in hypercholesterolaemia.

Intestinal FGF15 regulates bile acid and cholesterol metabolism but not glucose and energy balance.

Fibroblast growth factor 15/19 (FGF15/19, mouse/human ortholog) is expressed in the ileal enterocytes of the small intestine and released postprandially in response to bile acid absorption. Previous reports of FGF15-/- mice have limited our understanding of gut-specific FGF15's role in metabolism. Therefore, we studied the role of endogenous gut-derived FGF15 in bile acid, cholesterol, glucose, and energy balance. We found that circulating levels of FGF19 were reduced in individuals with obesity and comorbidities, such as type 2 diabetes and metabolic dysfunction-associated fatty liver disease. Gene expression analysis of ileal FGF15-positive cells revealed differential expression during the obesogenic state. We fed standard chow or a high-fat metabolic dysfunction-associated steatohepatitis-inducing diet to control and intestine-derived FGF15-knockout (FGF15INT-KO) mice. Control and FGF15INT-KO mice gained similar body weight and adiposity and did not show genotype-specific differences in glucose, mixed meal, pyruvate, and glycerol tolerance. FGF15INT-KO mice had increased systemic bile acid levels but decreased cholesterol levels, pointing to a primary role for gut-derived FGF15 in regulating bile acid and cholesterol metabolism when exposed to obesogenic diet. These studies show that intestinal FGF15 plays a specific role in bile acid and cholesterol metabolism regulation but is not essential for energy and glucose balance.

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.

Mechanism of Tougu Xiaotong Capsules in delaying degeneration of osteoarthritis by regulating cholesterol metabolism in chondrocytes through lncRNA MALAT1

From the perspective of lncRNA MALAT1 regulating cholesterol metabolism in chondrocytes, this paper explores the effect and mechanism of Tougu Xiaotong Capsules(TGXTC) in delaying the degeneration of osteoarthritis. After one week of adaptive feeding, 48(8-week-old) C57BL/6 mice were randomly divided into a blank group(12 mice) and a model group(36 mice) by random number table method. The mice in the model group were anesthetized by inhalation of 5% isoflurane, and the OA model was induced by Hulth method. The experiment randomly divided the mice into a model group(12 mice), a drug-positive group(taururso-deoxycholic acid)(12 mice), and a TGXTC group(12 mice). The drug-positive group was given 500 mg·kg~(-1) taurodeoxycholic acid by intragastric administration. TGXTC group was given TGXTC 368 mg·kg~(-1) by gavage. The blank group and model group were given the same amount of normal saline for four weeks. After the intervention, the mice in each group were killed under anesthesia, and the knee cartilage tissue was separated and collected. The morphologic changes of knee cartilage were observed. The level of lncRNA MALAT1 in the cartilage tissue was detected by real-time PCR. The protein expressions of ABCA1, ApoA1, LXRβ, CHOP, and caspase-3 in mouse articular cartilage were detected by Western blot. Lentivirus-coated plasmid was used to transfect mouse chondrocytes with sh-MALAT1. The gene levels of lncRNA MALAT1 in mouse chondrocytes transfected with sh-MALAT1 were detected by real-time PCR. Western blot was used to detect the effect of TGXTC on the protein content of ABCA1, ApoA1, LXRβ, CHOP, and caspase-3 in thapsigargin(TG)-induced mouse chondrocytes after lncRNA MALAT1 knockdown. Flow cytometry was used to detect the effect of TGXTC on apoptosis of TG-induced mouse chondrocytes after lncRNA MALAT1 knockdown. The results of HE and saffranine O staining showed that compared with the model group, the structure of the cartilage layer was basically intact; the damage degree of joint structure was significantly improved, and the cartilage matrix was significantly enhanced by saffranine O staining in the TGXTC group and drug-positive group. Compared with the model group, the lncRNA MALAT1 level was significantly decreased in the TGXTC group and drug-positive group. Compared with the model group, the protein content of ABCA1, ApoA1, and LXRβ was significantly increased, while that of CHOP and caspase-3 in the TGXTC group and drug-positive group significantly decreased. Compared with the TG group, the lncRNA MALAT1 level in the TG+sh-MALAT1 group was decreased. The lncRNA MALAT1 level in the TG+sh-MA-LAT1+TGXTC group was increased compared with the TG+TGXTC group. Western blot results showed that compared with the model group, protein expressions of ABCA1, ApoA1, LXRβ, CHOP, and caspase-3 in the TGXTC group were significantly decreased, after lncRNA MALAT1 knockdown, the regulation and apoptosis of ABCA1, ApoA1, LXRβ, CHOP, and caspase-3 in TG-induced mouse chondrocytes were weakened by TGXTC. TGXTC can improve the disorder of cholesterol metabolism in OA chondrocytes and delay OA degeneration, which is closely related to the regulation of lncRNA MALAT1.

Molecular Mechanisms Associated with the Development of the Metritis Complex in Dairy Cattle.

The metritis complex (MC), a group of post-partum uterine diseases, is associated with increased treatment costs and reduced milk yield and fertility. The goal of this study was to identify genetic variants, genes, or genomic regions that modulate MC disease. A genome-wide association study was performed using a single-locus mixed linear model of 1967 genotypes (624,460 SNPs) and metritis complex records. Then, in-silico functional analyses were performed to detect biological mechanisms and pathways associated with the development of MC. The ATP8A2, COX16, AMN, and TRAF3 genes, located on chromosomes 12, 10, and 21, were associated with MC at p ≤ 0.0001. These genes are involved in the regulation of cholesterol metabolism in the stromal tissue of the uterus, which can be directly associated with the mode of transmission for pathogens causing the metritis complex. The modulation of cholesterol abundance alters the efficiency of virulence factors and may affect the susceptibility of the host to infection. The SIPA1L1, DEPDC5, and RNF122 genes were also significantly associated with MC at p ≤ 0.0001 and are involved in the PI3k-Akt pathway, responsible for activating the autophagic processes. Thus, the dysregulation of these genes allows for unhindered bacterial invasion, replication, and survival within the endometrium.

Abstract 3085: Cholesterol sulfotransferase SULT2B1b suppresses prostate tumor growth and regulates cholesterol metabolism in prostate cancer cells

Abstract Prostate cancer (PrCa) ranks as the second leading cause of cancer death in males in the United States. The 5-year survival rate drops drastically from 100% in patients with early-stage confined PrCa to 30% in those with advanced metastatic PrCa. Patients with advanced PrCa face limited long-term treatment options, often developing resistance to androgen-deprivation therapy and chemotherapy. Identifying and targeting pivotal molecules or pathways in advanced PrCa can substantially enhance patient survival. Our previous findings unveiled an inverse relationship between cholesterol sulfotransferase SULT2B1b and the severity of human PrCa. The highest levels of SULT2B1b were observed in the epithelium of normal prostates, with a progressive decrease as cancer advanced. The lowest levels were found in the most advanced metastatic samples. This study aims to determine whether SULT2B1b performs any active and critical functions in PrCa progression and assess whether it regulates cholesterol metabolism in PrCa cells. We generated SULT2B1b knockout (KO) clones from mouse PrCa cell line MyC-CaP and established inducible SULT2B1b overexpression lines from androgen receptor (AR)+ LNCaP and AR- PC3 human PrCa cells. These modified mouse and human cells were implanted into syngeneic FVB mice and immunodeficient NRG mice, respectively. MyC-CaP KO cells formed significantly larger tumors compared to parental cells, accompanied by reduced survival rates. In contrast, both LNCaP and PC3 tumors with induced SULT2B1b exhibited smaller sizes compared to control tumors, leading to improved survival rates. To investigate the impact of SULT2B1b on cholesterol metabolism and the underlying mechanisms behind SULT2B1b-regulated tumor growth, we examined genes related to lipoprotein signaling and cholesterol metabolism in MyC-CaP SULT2B1b KO cells using PCR arrays and qRT-PCR. Genes responsible for cholesterol uptake and synthesis (e.g. Ldlr, Cyp51, Sorl1, Pcsk9 and Insig1) were among the top upregulated genes, while genes controlling cholesterol efflux (e.g. Abca1) and esterification (e.g. Soat1 and Soat2) were downregulated in KO cells. Consistent with these gene expression patterns, intracellular cholesterol levels significantly increased in KO cells. Interestingly, although SULT2B1b did not affect cell proliferation under normal conditions, KO cells exhibited faster growth than parental cells when cultured in lipid-depleted or charcoal-stripped media, possibly due to altered intracellular cholesterol levels. In summary, these findings align with the expression pattern of SULT2B1b in human PrCa, demonstrating that SULT2B1b inhibits tumor growth, whereas its removal promotes tumor growth. This suggests SULT2B1b may serve as a critical tumor suppressor in PrCa. Its modulation of tumor growth may occur through the regulation of cholesterol metabolism. Citation Format: Jiang Yang, Dilinaer Wusiman, Timothy L. Ratliff. Cholesterol sulfotransferase SULT2B1b suppresses prostate tumor growth and regulates cholesterol metabolism in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3085.

Abstract 632: AKT supports cancer cell survival through modulation of cholesterol homeostasis

Abstract AKT is a critical effector kinase downstream of PI3K activation. It has been shown to regulate a variety of cellular processes important for homeostasis, many of which are altered during oncogenesis. Not surprisingly, AKT is constitutively activated in a large number of human cancers, and has consequently been pursued as a therapeutic target for many years. Some of these functions are directly involved in establishing one or more hallmarks of cancer including sustained proliferative signaling, resisting cell death, and reprogrammed cellular metabolism. Although AKT inhibitors have demonstrated clinical benefit (most recently in a phase III trial) in combination with other therapies, single agent activity has been limited to a few cases with relatively infrequent activating AKT1 mutations. We have previously proposed that the clear disconnect between the high frequency of AKT activation in cancer and the lack of broad clinical activity of AKT inhibitors is due, at least in part, to the inability of existing compounds to block non-catalytic functions. We have found that while allosteric AKT inhibitors are partial suppressors of these functions, ATP-competitive inhibitors fail to suppress these functions to any significant extent. We now provide evidence that one important non-catalytic function of AKT that impinges on its oncogenic function is the regulation of cholesterol metabolism. We show that AKT represses the activation of LXRβ, thereby maintaining a level of intracellular cholesterol that is compatible with cancer cell viability, and that this repression does not require catalytic activity. Consistently, we find that allosteric AKT inhibitors induce LXRβ activation, and that genetic or pharmacological suppression of LXRβ function limit the growth inhibiting effects of these drugs. Our findings suggest that through a kinase-independent activity, AKT may play a significant role in the regulation of cholesterol homeostasis, and that the therapeutic potential of AKT inhibitors could be broaden by optimizing their ability to interfere with these functions. Citation Format: Igor Vivanco, Khine N. Myint, Sean Wallace, Glorianne Lazaro, Eleftherios Kostaras, Nikolaos Palaskas. AKT supports cancer cell survival through modulation of cholesterol homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 632.

Abstract 364: Targeting LILRB1 to sensitize human myeloma to ferroptosis through disrupting cholesterol homeostasis

Abstract Multiple myeloma (MM) is a hematologic malignancy characterized by the uncontrolled clonal proliferation of plasma cells in the bone marrow (BM). Despite the demonstrated benefits of novel therapies, relapses are frequent, and acquired resistance to MM treatment eventually emerges in most, if not all, patients. MM patients who suffer more aggressive progression usually result in poorer survival. The genes driving such unfavored outcomes in MM have not been fully understood. Therefore, there is an urgent need to identify the genes and mechanisms that contribute to the aggressive behaviors of MM in order to develop improved therapeutic strategies for the disease. To discover new potential therapeutic targets for MM patients, we analyzed gene-profiling data of MM patients and identified leukocyte immunoglobulin-like receptor B1 (LILRB1), a transmembrane receptor conducting negative immune response, as one of the top-ranked genes associated with poor prognosis. LILRB1 on immune cells was reported to bind to its ligand, b2-microglobulin, on tumor cells. This interaction leads to immune suppression responses in various immune cells. However, the function of tumor-derived LILRB1 in tumor biology remains unclear and the role of LILRB1 in MM has been poorly studied. Our further analysis of the patient data demonstrated that MM patients with high expression of LILRB1 are closely related to higher MM recurrence rates, advanced stages, and lower survival rates, indicating that LILRB1 is an important player in MM pathogenesis and thus a promising target for MM therapy. Interestingly, RNA-seq data of human MM cells from the BM of MM-bearing mice showed that knockdown (KD) of LILRB1 activated cholesterol metabolism- and ferroptosis-related pathways in murine BM. Moreover, KD of LILRB1 significantly impaired tumor progression in murine models. Consistently, in vitro experiments also demonstrated that LILRB1 protected MM cells from ferroptosis inducer-caused lipid ROS and ferroptotic cell death, indicating that LILRB1 promotes the progression of MM cells by protecting them from ferroptosis. Further study were then conducted to reveal the underlying mechanism. LC-MS/MS analysis followed by co-IP demonstrated that LDLRAP1, an adaptor protein that interacts with LDLR, bound with LILRB1 and formed a complex together with LDLR. KD of LILRB1 inhibited LDL uptake by disrupting the interaction between LDLR and LDLRAP1 and triggering the compensatory cholesterol synthesis by upregulating the expression of SQLE that converted squalene to (S)-2,3-epoxysqualene. With less squalene to protect MM cells from lipid peroxidation, MM cells were more susceptible to the induction of ferroptosis. Thus, this study uncovers a novel function of LILRB1 in regulating cholesterol metabolism and protecting MM cells from ferroptosis during MM progression and implicates LILRB1 as a promising therapeutic target for MM patients. Citation Format: Miao Xian, Qing Yi, Qiang Wang, Liuling Xiao, Ling Zhong, chuanchao zhang, yabo Li, Jianfei Qian. Targeting LILRB1 to sensitize human myeloma to ferroptosis through disrupting cholesterol homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 364.

Liver X Receptors (LXRs) in cancer-an Eagle's view on molecular insights and therapeutic opportunities.

Cancer has become a serious health burden that results in high incidence and mortality rates every year, mainly due to various molecular alterations inside the cell. Liver X receptors (LXRs) dysregulation is one among them that plays a vital role in cholesterol metabolism, lipid metabolism and inflammation and also plays a crucial role in various diseases such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular diseases, Type 2 diabetes, osteoporosis, and cancer. Studies report that the activation of LXRs inhibits cancer growth by inhibiting cellular proliferation, inducing apoptosis and autophagy, regulating cholesterol metabolism, various signalling pathways such as Wnt, and PI3K/AKT, modulating the expression levels of cell-cycle regulators, and promoting antitumor immunity inside the tumor microenvironment. In this review, we have discussed the role, structure, and functions of LXRs and also summarized their ligands along with their mechanism of action. In addition, the role of LXRs in various cancers, tumor immunity and tumor microenvironment (TME) along with the importance of precision medicine in LXR-targeted therapies has been discussed to emphasize the LXRs as potent targets for the development of novel cancer therapeutics.

Arenobufagin modulation of PCSK9-mediated cholesterol metabolism induces tumor-associated macrophages polarisation to inhibit hepatocellular carcinoma progression

BackgroundThe tumor microenvironment (TME) of hepatocellular carcinoma is heterogeneous enough to be prone to drug resistance and multidrug resistance during treatment, and reprogramming of cholesterol metabolism in TME mediates tumor-associated macrophages (TAMs) polarization, which has an impact on the regulation of malignant tumor progression. Arenobufagin (ARBU) was extracted and isolated from toad venom (purity ≥98 %), which is the main active ingredient of the traditional Chinese medicine Chan'su with good anti-tumor effects. PurposeTo investigate the regulatory effect of ARBU on lipid metabolism in tumor microenvironment, interfere with macrophage polarization, and determine its mechanism of action on liver cancer progression. MethodsIn this study, the inhibitory effect of ARBU on the proliferation of Hepa1–6 in C57 mice and the safety of administration were evaluated by establishing a transplanted tumor model of Hepa1–6 hepatocellular carcinoma mice and using 5-FU as a positive control drug. In addition, we constructed a co-culture system of Hepa1–6 cells and primary mouse macrophages to study the effects of ARBU on the polarization phenotypic transformation of macrophages and the proliferation and migration of hepatoma cells. The influence of ARBU on the metabolism of lipids in the hepatocellular carcinoma mouse model was investigated by combining it with lipidomics technology. The influence of ARBU on the PCSK9/LDL-R signaling pathway and macrophage polarization, which regulate cholesterol metabolism, was tested by using qRT-PCR, gene editing, IF, and WB. ConclusionARBU significantly inhibited the proliferation of Hepa1–6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration.

Cheong-sang-gyeon-tong-tang improves hepatic steatosis by regulating cholesterol metabolism

Cheong-sang-gyeon-tong-tang improves hepatic steatosis by regulating cholesterol metabolism

A gut-derived hormone regulates cholesterol metabolism

The reciprocal coordination between cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver is essential for maintaining cholesterol homeostasis, yet the mechanisms governing the opposing regulation of these processes remain poorly understood. Here, we identify a hormone, Cholesin, which is capable of inhibiting cholesterol synthesis in the liver, leading to a reduction in circulating cholesterol levels. Cholesin is encoded by a gene with a previously unknown function (C7orf50 in humans; 3110082I17Rik in mice). It is secreted from the intestine in response to cholesterol absorption and binds to GPR146, an orphan G-protein-coupled receptor, exerting antagonistic downstream effects by inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver. Therefore, our results demonstrate that the Cholesin-GPR146 axis mediates the inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. This discovered hormone, Cholesin, holds promise as an effective agent in combating hypercholesterolemia and atherosclerosis.

Mining cholesterol genes from thousands of mouse livers identifies aldolase C as a regulator of cholesterol biosynthesis

The availability of genome-wide transcriptomic and proteomic datasets is ever-increasing and often not used beyond initial publication. Here, we applied module-based coexpression network analysis to a comprehensive catalog of 35 mouse genome-wide liver expression datasets (encompassing more than 3800 mice) with the goal of identifying and validating unknown genes involved in cholesterol metabolism. From these 35 datasets, we identified a conserved module of genes enriched with cholesterol biosynthetic genes. Using a systematic approach across the 35 datasets, we identified three genes (Rdh11, Echdc1, and Aldoc) with no known role in cholesterol metabolism. We then performed functional validation studies and show that each gene is capable of regulating cholesterol metabolism. For the glycolytic gene, Aldoc, we demonstrate that it contributes to de novo cholesterol biosynthesis and regulates cholesterol and triglyceride levels in mice. As Aldoc is located within a genome-wide significant genome-wide association studies locus for human plasma cholesterol levels, our studies establish Aldoc as a causal gene within this locus. Through our work, we develop a framework for leveraging mouse genome-wide liver datasets for identifying and validating genes involved in cholesterol metabolism.

Cholesterol metabolism: physiological regulation and diseases.

Cholesterol homeostasis is crucial for cellular and systemic function. The disorder of cholesterol metabolism not only accelerates the onset of cardiovascular disease (CVD) but is also the fundamental cause of other ailments. The regulation of cholesterol metabolism in the human is an extremely complex process. Due to the dynamic balance between cholesterol synthesis, intake, efflux and storage, cholesterol metabolism generally remains secure. Disruption of any of these links is likely to have adverse effects on the body. At present, increasing evidence suggests that abnormal cholesterol metabolism is closely related to various systemic diseases. However, the exact mechanism by which cholesterol metabolism contributes to disease pathogenesis remains unclear, and there are still unknown factors. In this review, we outline the metabolic process of cholesterol in the human body, especially reverse cholesteroltransport (RCT). Then, we discuss separately the impact of abnormal cholesterol metabolism on common diseases and potential therapeutic targets for each disease, including CVD, tumors, neurological diseases, and immune system diseases. At the end of this review, we focus on the effect of cholesterol metabolism on eye diseases. In short, we hope to provide more new ideas for the pathogenesis and treatment of diseases from the perspective of cholesterol.

Tumour-associated macrophage-derived DOCK7-enriched extracellular vesicles drive tumour metastasis in colorectal cancer via the RAC1/ABCA1 axis.

Metastasis accounts for the majority of deaths among patients with colorectal cancer (CRC). Here, the regulatory role of tumour-associated macrophages (TAMs) in CRC metastasis was explored. Immunohistochemical (IHC) analysis of the TAM biomarker CD163 was conducted to evaluate TAM infiltration in CRC. Transwell assays and an ectopic liver metastasis model were established to evaluate the metastatic ability of tumour cells. RNA sequencing (RNA-seq) and liquid chromatography-mass spectrometry (LC-MS) were applied to identify the differentially expressed genes and proteins in CRC cells and in TAM-derived extracellular vesicles (EVs). Cholesterol content measurement, a membrane fluidity assay and filipin staining were performed to evaluate cholesterol efflux in CRC cells. Our results showed that TAM infiltration is positively correlated with CRC metastasis. TAMs can facilitate the migration and invasion of MC-38 and CT-26 cells via EVs. According to the RNA-seq data, TAM-EVs increase cholesterol efflux and enhance membrane fluidity in CRC cells by regulating ABCA1 expression, thus affecting the motility of CRC cells. Mechanistically, DOCK7 packaged in TAM-EVs can activate RAC1 in CRC cells and subsequently upregulate ABCA1 expression by phosphorylating AKT and FOXO1. Moreover, IHC analysis of ABCA1 in patients with liver-metastatic CRC indicated that ABCA1 expression is significantly greater in metastatic liver nodules than in primary CRC tumours. Overall, our findings suggest that DOCK7 delivered via TAM-EVs could regulate cholesterol metabolism in CRC cells and CRC cell metastasis through the RAC1/AKT/FOXO1/ABCA1 axis. DOCK7 could thus be a new therapeutic target for controlling CRC metastasis.

Regulating Cholesterol in Tumorigenesis: A Novel Paradigm for Tumor Nanotherapeutics.

During the past decade, "membrane lipid therapy", which involves the regulation of the structure and function of tumor cell plasma membranes, has emerged as a new strategy for cancer treatment. Cholesterol is an important component of the tumor plasma membrane and serves an essential role in tumor initiation and progression. This review elucidates the role of cholesterol in tumorigenesis (including tumor cell proliferation, invasion/metastasis, drug resistance, and immunosuppressive microenvironment) and elaborates on the potential therapeutic targets for tumor treatment by regulating cholesterol. More meaningfully, this review provides an overview of cholesterol-integrated membrane lipid nanotherapeutics for cancer therapy through cholesterol regulation. These strategies include cholesterol biosynthesis interference, cholesterol uptake disruption, cholesterol metabolism regulation, cholesterol depletion, and cholesterol-based combination treatments. In summary, this review demonstrates the tumor nanotherapeutics based on cholesterol regulation, which will provide a reference for the further development of "membrane lipid therapy" for tumors.

Nanoparticle Targeting in Chemo-Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance.

Platinum (Pt)-based chemotherapy is the main treatment for ovarian cancer (OC); however, most patients develop Pt resistance (Pt-R). This work shows that Pt-R OC cells increase intracellular cholesterol through uptake via the HDL receptor, scavenger receptor type B-1 (SR-B1). SR-B1 blockade using synthetic cholesterol-poor HDL-like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death and inhibition of tumor growth. Reduced cholesterol accumulation in cancer cells induces lipid oxidative stress through the reduction of glutathione peroxidase 4 (GPx4) leading to ferroptosis. In turn, GPx4 depletion induces decreased cholesterol uptake through SR-B1 and re-sensitizes OC cells to Pt. Mechanistically, GPx4 knockdown causes lower expression of the histone acetyltransferase EP300, leading to reduced deposition of histone H3 lysine 27 acetylation (H3K27Ac) on the sterol regulatory element binding transcription factor 2 (SREBF2) promoter and suppressing expression of this key transcription factor involved in the regulation of cholesterol metabolism. SREBF2downregulation leads to decreased SR-B1 expression and diminished cholesterol uptake. Thus, chemoresistance and cancer cell survival under high ROS burden obligates high GPx4 and SR-B1 expression through SREBF2. Targeting SR-B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt-R OC.

Diosgenin as a substitute for cholesterol alleviates NAFLD by affecting CYP7A1 and NPC1L1-related pathway

BackgroundNonalcoholic fatty liver disease (NAFLD) rapidly becomes the leading cause of end-stage liver disease or liver transplantation. Nowadays, there has no approved drug for NAFLD treatment. Diosgenin as the structural analogue of cholesterol attenuates hypercholesterolemia by inhibiting cholesterol metabolism, which is an important pathogenesis in NAFLD progression. However, there has been no few report concerning its effects on NAFLD so far. MethodsUsing a high-fat diet & 10% fructose-feeding mice, we evaluated the anti-NAFLD effects of diosgenin. Transcriptome sequencing, LC/MS analysis, molecular docking simulation, molecular dynamics simulations and Luci fluorescent reporter gene analysis were used to evaluate pathways related to cholesterol metabolism. ResultsDiosgenin treatment ameliorated hepatic dysfunction and inhibited NAFLD formation including lipid accumulation, inflammation aggregation and fibrosis formation through regulating cholesterol metabolism. For the first time, diosgenin was structurally similar to cholesterol, down-regulated expression of CYP7A1 and regulated cholesterol metabolism in the liver (p < 0.01) and further affecting bile acids like CDCA, CA and TCA in the liver and feces. Besides, diosgenin decreased expression of NPC1L1 and suppressed cholesterol transport (p < 0.05). Molecular docking and molecular dynamics further proved that diosgenin was more strongly bound to CYP7A1. Luci fluorescent reporter gene analysis revealed that diosgenin concentration-dependently inhibited the enzymes activity of CYP7A1. ConclusionOur findings demonstrated that diosgenin was identified as a specific regulator of cholesterol metabolism, which pave way for the design of novel clinical therapeutic strategies.

Current Understanding of PCSK9 and Its Relevance to Cancer Prognosis and Immune Therapy: A Review.

The effectiveness of immunotherapy for most cancer patients remains low, with approximately 10-30% of those treated surviving. Thus, much effort is being put into finding new ways to improve immune checkpoint therapy. Our review concludes that inhibition of proprotein convertase subtilisin/Kexin type 9 (PCSK9), which plays a critical role in regulating cholesterol metabolism, can cause movement of T cells toward tumors, with increased sensitivity to immune checkpoint therapies. We searched PubMed, NCBI, Scopus, and Google Scholar for the published articles without limitations on publication dates. We used the following terms: "PCSK9", "Cancer", "Immune Checkpoint", and "Cancer Prognosis" in the title and/or abstract. Our search initially revealed 600 records on the subject and stored them in the used databases under EndNote X8 management software. A total of 161 articles were selected and through a careful review, 76 were included in our research. We concluded that PCSK9 reduces the number of LDL receptors (LDL-R) on the cell surface, which is linked to its ability to regulate cholesterol levels in the body. Also, we discuss how suppressing PCSK9 leads to the MHC-1 accumulation on the surface of cancer cells, which results in T lymphocyte invasion. Finally, we believe that inhibiting PCSK9 may be an effective strategy for improving cancer immunotherapy.

The role of cholesterol metabolism in lung cancer.

Elevated serum cholesterol metabolism is associated with a reduced risk of lung cancer. Disrupted cholesterol metabolism is evident in both lung cancer patients and tumor cells. Inhibiting tumor cell cholesterol uptake or biosynthesis pathways, through the modulation of receptors and enzymes such as liver X receptor and sterol-regulatory element binding protein 2, effectively restrains lung tumor growth. Similarly, promoting cholesterol excretion yields comparable effects. Cholesterol metabolites, including oxysterols and isoprenoids, play a crucial role in regulating cholesterol metabolism within tumor cells, consequently impacting cancer progression. In lung cancer patients, both the cholesterol levels in the tumor microenvironment and within tumor cells significantly influence cell growth, proliferation, and metastasis. The effects of cholesterol metabolism are further mediated by the reprogramming of immune cells such as T cells, B cells, macrophages, myeloid-derived suppressor cells, among others. Ongoing research is investigating drugs targeting cholesterol metabolism for clinical treatments. Statins, targeting the cholesterol biosynthesis pathway, are widely employed in lung cancer treatment, either as standalone agents or in combination with other drugs. Additionally, drugs focusing on cholesterol transportation have shown promise as effective therapies for lung cancer. In this review, we summarized current research regarding the rule of cholesterol metabolism and therapeutic advances in lung cancer.