what is cholesterol?
Cholesterol is a lipid, or fat-like substance, that is found in the blood and in all the cells of the body. It plays a crucial role in various biological functions, including the production of hormones, the formation of cell membranes, and the synthesis of vitamin D. However, excessive amounts of cholesterol in the blood can be harmful, as it can build up in the arteries and increase the risk of heart disease.
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Cholesterol is mainly of two types: low-density lipoprotein (LDL) cholesterol, also known as "bad" cholesterol, and high-density lipoprotein (HDL) cholesterol, often referred to as "good" cholesterol. LDL cholesterol is responsible for depositing cholesterol in the arteries, while HDL cholesterol helps remove it, thus reducing the risk of atherosclerosis.
Maintaining healthy cholesterol levels is important for overall health. This can be achieved through a balanced diet, regular exercise, and, in some cases, medication prescribed by a healthcare professional. A diet low in saturated fats and cholesterol, and rich in fruits, vegetables, whole grains, and lean protein can help lower LDL cholesterol levels. Additionally, regular exercise can help raise HDL cholesterol levels and improve cardiovascular health.
The physiological significance of cholesterol
Cholesterol plays a pivotal role in numerous physiological processes within the human body. It is a crucial component of cell membranes, providing structural stability and integrity to the cells. The membranes of all animal cells contain cholesterol, which helps maintain their fluidity and permeability, allowing essential substances to pass through while keeping out harmful ones.
Moreover, cholesterol serves as a precursor for the synthesis of various hormones, including sex hormones like testosterone and estrogen, as well as adrenal hormones like cortisol. It is also essential for the production of vitamin D in the skin when exposed to sunlight.
Cholesterol also plays a role in the metabolism of fats, assisting in the digestion and absorption of dietary fats. It is involved in the formation of bile acids, which help emulsify fats in the small intestine, enabling their breakdown and absorption into the bloodstream.
Study reveals new mechanism of cholesterol metabolism regulating macrophage anti-tumor
On April 19, Wang Hongyan's research group at the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, in collaboration with Shanghai University, Fudan University and Shanghai Jiao Tong University, published an online paper titled 25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolism in Immunity. Research paper on reprogramming to educate immunosuppressive macrophages. This study discovered the key cholesterol metabolism enzyme CH25H and metabolite 25-HC that inhibit inflammatory macrophage activation, providing a new metabolic target for tumor immunotherapy targeting macrophages, and proposing a method for reprogramming cholesterol metabolism to regulate innate immunity. gained new insights.
In response to pathogenic microbial infection, macrophages can secrete pro-inflammatory cytokines and interferons to eliminate pathogens. They can respond to the stimulation of the tumor microenvironment or the cytokine IL-4/IL-13 and express anti-inflammatory cytokines and arginase ( Arg1) to consume arginine in the microenvironment and block T cell proliferation and tumor killing functions. Cholesterol metabolites are important components of cell membranes and organelle membranes and can regulate cell proliferation, migration, inflammation and other functions, while cholesterol disorders are associated with a variety of diseases. Earlier, studies found that the accumulation of 7-dehydrocholesterol can promote the production of type I interferon, which is opposite to the function of cholesterol inhibiting interferon. Cholesterol is oxidized to produce 25-hydroxycholesterol (25-HC); in turn, 25-HC is oxidized to produce 7a,25-hydroxycholesterol. 25-HC and 7a,25-hydroxycholesterol are elevated in the peripheral blood of patients with the autoimmune disease systemic lupus erythematosus (SLE). 7a,25-hydroxycholesterol reduces the onset of SLE by binding to and activating the G protein-coupled receptor EBI2 on the surface of macrophages, inhibiting the expression of various chemokines and inflammatory factors. However, how cholesterol metabolism regulates the immunosuppressive functions and molecular mechanisms of tumor-associated macrophages (TAMs) remains unclear.
The team used three types of immunosuppressive macrophages, namely M2 macrophages stimulated by cytokines IL-4 and IL-13, macrophages incubated in conditioned medium of the liver cancer cell line Hepa1-6, and solid tumor tissues. The sorted TAMs were screened for the expression levels of cholesterol metabolism enzymes, and it was found that cholesterol 25-hydroxylase (CH25H) was induced to be highly expressed. Previous studies have confirmed that infection promotes the high expression of CH25H and oxidizes cholesterol to 25-HC, thereby blocking the virus from invading host cells through membrane fusion. This study found increased levels of oxysterol 25-HC in M2 macrophages, TAMs, and tumor tissues. By analyzing published data, scRNA-seq found that CH25H is highly expressed in MARCO+TAMs or LYVE1+TAMs in a variety of solid tumor tissues and is negatively correlated with the prognosis of tumor patients.
Further, studies have found that lactic acid in the tumor microenvironment can induce Ch25h and the cytokine IL-4/IL-13 regulates Ch25h transcription through the transcription factor STAT6. The accumulated 25-HC accumulates in macrophage lysosomes and competes with cholesterol to bind to the lysosome-localized signaling protein GPR155 to inhibit mTORC1 activation. By enhancing the activation of AMPKa, the transcription factor STAT6 is phosphorylated at serine 564 to enhance the transcriptional activity of STAT6 and promote macrophages to produce more Arg1 and anti-inflammatory factors. In macrophages, knocking out Ch25h can reverse the immunosuppressive function of TAM and block the development of various subcutaneous tumors, accompanied by enhanced T cell infiltration and activation and high expression of the immune checkpoint PD-1 in tumor tissues. Therefore, the combination of anti-PD1 monoclonal antibodies can enhance the anti-tumor effect.
In summary, targeting cholesterol oxidase CH25H promotes the transformation of "cold tumors" into "hot tumors" and combines immune checkpoints to improve the efficacy of tumor immunity. The team proposed the concept of locating oxysterols and cholesterol in lysosomes and the mutual balance between the two to regulate macrophage fate. At the same time, the team expanded the cholesterol oxidase CH25H and oxysterol 25-HC from the field of infection to the field of tumor immunotherapy.