As it happens a new study brought up the idea that antagonists of CD36 may be considered as senomorphic agents and CD36 acts as a major regulator of SASP. After looking into the matter a bit more it became apparent that its role conforms pretty well to earlier hypotheses and CD36 is most likely to be at the heart of POIS. Actually a lot of the supplements frequently used by members can be considered antagonists of CD36, thus senomorphic in nature. Estrogen receptor beta activation can downregulate CD36 through the ERB-PPARG-CD36 pathway, which could mean that even ERB agonists may be considered at least partially senomorphic. CD36 also fits well into the earlier model of metabolic syndrome, especially so as SIRT1 activators inhibit CD36. Long-term (about 2 weeks) overexpression of CD36 may establish senescence and SASP. It is not clear how reversible this state is, but it is interesting to note that two of our members presumably managed to cure themselves by the combination of mastic gum, oregano oil and medicinal mushrooms in a few weeks time. As all of these may act as CD36 antagonist, a potent suppression can be expected, which may lead to long-term changes. It has to be noted that different CD36 antagonists provided varying result for members (e.g. aged garlic), which may be related to SASP heterogeneity or receptor polymorphisms. Nevertheless a good strategy could be to combine a few effective CD36 inhibitors and hopefully it can be a blast on POIS. Of course there are some inconsistencies here-and-there as usual, but the theoretical evidence and both my and other POISer's experiences are so convergent that it practically proves that most POIS cases stem from cellular senescence of sexual organs and thus POIS can be clearly declared as a subclass of SASP. CD36 is also significantly elevated in severe covid-19, which may establish the connection to post-covid. It can also explain why we react adversely to coffee or gluten. Some controversy could be the role of p21 which is also involved in senescence development. P21 is induced by ERB, however Sirt1 activation inhibits this factor. A possible explanation may be that ERB also initiates apoptosis of senescent cells and acts as a senolytic, but who knows. Even so a similar problem exist with hTERT inhibition, as most senolytics are also known inhibitors of hTERT.
See the other thread for possible relations with hTERT and ERB:
https://poiscenter.com/forums/index.php?topic=4061.msg44628#msg44628Also don't forget to check the model of metabolic syndrome:
https://poiscenter.com/forums/index.php?topic=3986.msg42530#msg42530CD36 initiates the secretory phenotype during the establishment of cellular senescence. Cellular senescence is a unique cell fate characterized by stable proliferative arrest and the extensive production and secretion of various inflammatory proteins, a phenomenon known as the senescence-associated secretory phenotype (SASP). Ectopic CD36 expression in dividing mammalian cells is sufficient to initiate the production of a large subset of the known SASP components via activation of canonical Src–p38–NF-kB signaling, resulting in the onset of a full senescent state.
Senescent cells have increased expression of at least one cyclin-dependent kinase (CDK) inhibitor, typically p16 or p21, which functions to activate the Rb tumor suppressor, resulting in cell cycle arrest.
Upon senescence initiation, two transcription factors normally present in immune cells, NF-kB and CEBPbeta, are activated to promote the transcription of a set of relatively conserved pro-inflammatory cytokines, chemokines, growth factors, and proteases. Some canonical signal transduction cascades, such as the mTOR and p38 MAPK pathways, have been shown to stimulate NF-kB and SASP formation during senescence.
Previous studies have identified diverse CD36 ligands including collagen, thrombospondin, and various lipoproteins and lipids that bind CD36 in order to regulate vascular and adipose homeostasis.
Sustained exposure of CD36 to ligand drives pro-inflammatory cytokine production and cell cycle arrest in order to establish the overall senescent state in both epithelial cells and fibroblasts. Finally, loss-of-function experiments demonstrate that CD36 is strictly required for NF-kB phosphorylation and SASP initiation and maintenance during both oncogene- and chemical-induced senescence.
CD36 had a ~100-fold induction in aged mice, indicating a strong correlation between CD36 induction and bronchial cell senescence and aging.
Many well-recognized conventional SASP components were found to be consistently produced upon CD36 expression, including interleukin 6 (IL-6) and interleukin 8 (IL-8).
Long-term CD36 expression promotes a comprehensive senescent phenotype
Prolonged (14 days) CD36 expression led to a striking phenotype of cell cycle exit that was associated with increased levels of cyclin?dependent kinase inhibitors and SA-BGal activity.
The SASP comprises a combination of secreted molecules that collectively function to reinforce the overall senescent phenotype.
IL-6 administration produced a strong senescent phenotype in IMR90 fibroblasts, indicating cell type-specific differences in the ability of individual SASP components to induce senescence. At early time points, CD36 functions to drive NF-kB-mediated secretion of canonical SASP components, which in turn act in a feed-forward manner to promote stable cell cycle arrest and establish the senescent state.
Although CD36 knockdown did not rescue the cell cycle arrest or SA-BGal activity phenotypes caused by EGFR inhibition, we observed a major impairment in Src–p38–NF-kB activation after senescence induction when CD36 upregulation was suppressed. Consistent with this, a large cohort of SASP components was not induced during senescence after CD36 knockdown, and this subset largely coincides with the group of pro-inflammatory molecules induced by ectopic CD36 expression. These results demonstrate a functional requirement of CD36 for NF-kB-mediated SASP establishment in response to multiple senescent stimuli.
Here, we propose that the ability of senescent cells to adopt an immune-like secretory phenotype largely stems from their capacity to upregulate the expression of CD36 in response to various senescent stimuli.
CD36 is likely to be a more direct and rapid pathway for SASP activation in response to senescent stimuli. Indeed, nearly ten-fold CD36 upregulation was observed here only 6 h after senescence induction.https://www.embopress.org/doi/full/10.15252/embr.201745274During regeneration, senescence was reduced by inhibiting ROS. Sen cells showed altered lipid-transport and lipoprotein-remodelling traits, consistent with the ability of oxidative stress to generate lipotoxicity that triggers inflammation and fibrosis.
Depending on cell type and conditions, the number of SASP components ranged from 78 to 363, highlighting SASP diversity. Pathway enrichment identified two major functions: (1) inflammation, including complement and coagulation, innate-immune system, lipoprotein remodelling and cytokine and TNF/NF-kB signalling (Ccl2, Ccl7, Ccl8 and Isg15); and (2) fibrosis, including matrix organization and collagen metabolism, and TGFB signalling.
The SASP of Sen cells, transiently present in injured young muscles, mimics aged-like inflammageing, which is exacerbated in injured aged muscle.
Lipid transport, which is tightly associated with inflammatory responses, was consistently included in the inflammatory hallmark of Sen cells and the SASP in all conditions. Sen cells had more lipid droplets compared with NSen cells. Numerous lipid metabolism and lipid-transport genes, including Fabp3, Apoe, Star, Lpl, Cd68 and Cd36, were upregulated in all Sen cells.
FunRes generated a CD36 signalling network that predicted downstream activation of NF-kB and other inflammation/stress-related pathways, and downstream SASP components, such as Il6, Tgfb1, Mmp3, Igfbp5, Ccl2 and Cxcl10, suggesting that CD36 might regulate the in vivo senescence secretory program, affecting regeneration.
All three Sen cell types had higher CD36 protein expression in injured muscles.
CD36 blockade did not affect the number of senescent cells, but reduced several SASP proteins, and many coincided with SASP genes in Sen SCs, FAPs and MCs encoding chemokines, cytokines and matrix metalloproteinases (Ccl2, Ccl3, Il1b, Il10 and Mmp3).
CD36 blockade improved regeneration in both young and old muscles while reducing inflammation and fibrosis and these muscles showed increased force.
In injured muscle, senescent cells modified their normal niche counterparts by creating an aged-like inflamed microenvironment that hijacked their proliferative programs and blunted regeneration. Reducing the number of senescent cells (and therefore their inflammatory secretome) resumed stem-cell proliferation and enhanced muscle regeneration.
After injury, a subset of niche cells accumulates ROS and DNA damage beyond a threshold, which leads to senescence and regenerative failure.
The senescent state can be influenced in vivo by its trigger, the cell that senesces, its environment and its temporal resolution by the immune system, resulting in a wide spectrum of phenotypic features.
We revealed that two major conserved universal hallmarks define senescent cells: inflammation and fibrosis. We also determined that, depending on their lineage of origin, senescent cells have unique features that are preserved throughout life, indicating that they share universal programs while maintaining identity traits, and adapt to the idiosyncrasies of their origin and age. Thus, our study provided a better definition of senescence in vivo: despite being a state of irreversible arrest, senescence encompasses features of molecular diversity and dynamism (sensitive to the pass of time and mode of injury) as well as conserved hallmarks.
A reduction in the number of senescent cells improved regeneration as a result of attenuating inflammatory and fibrotic SASPs. Finally, we identified CD36 (a scavenger receptor that is related to lipid metabolism and inflammatory function) as a cell receptor acting as a senomorphic in vivo.https://www.nature.com/articles/s41586-022-05535-xThe results indicated that in response to diosgenin stimulation, ERB could suppress the expression of PPARG1/2, which may contribute to the inhibition of adipocyte differentiation.
Moreover, when ERB was inhibited by ICI182 780, reduction of mRNA expression of aP2 and CD36 by diosgenin was remarkably suppressed. PPARG regulates adipocyte differentiation through transcriptionally modulating a battery of target genes responsible for the terminal maturation of fat cell, including aP2 and CD36. The results indicated that activation of ERB could reduce PPARG expression, resulting in reduction of adipocyte differentiation.https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0041008X15300892Absence of ERB in adipose tissue results in exaggerated coactivator binding to a PPARG target promoter. We demonstrate for the first time a pro-diabetogenic function of the ERB. Moreover, our cell culture experiments indicate that ERB is a negative regulator of ligand-induced PPARG activity in vitro. The role of PPARG in the control of glucose homeostasis expands beyond its primary action in adipose tissue, and involves the regulation of adipocytokine production such as adiponectin, leptin, and resistin. Consistently, reduced PPARG activity has important metabolic and cardiovascular pathophysiological consequences leading to insulin resistance, diabetes and end organ damage. Importantly, PPARG is sharing a similar pool of cofactors with ERB which provides a platform for mutual interactions between these two NHRs.
BetaERKO mice exhibited augmented PPARG signaling in adipose tissue corresponding to increased food efficiency and significantly elevated RQ (respiratory quotient).
Adipose mRNA expression of PPARG target genes involved in triglycerides (TG) synthesis such as lipoprotein lipase (Lpl), phosphoenolpyruvate carboxykinase (PEPCK) and CD36 was significantly upregulated in BetaERKO mice.
These data suggest that the coactivators SRC1 and TIF2 are involved in the negative regulation of PPARG by ERB in vitro and in vivo.https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1000108Increases in expression of enzymes for fatty acid beta oxidation (MCAD, CPT1 etc.) via activation of PPARA, and mitochondrial capacity via activation of nuclear respiratory factor 1(NRF-1) and NRF-2 contribute to increased fatty acid oxidation. It was reported that the promoter region of CD36 and FATP1 contains a peroxisome proliferator-responsive element (PPRE).https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028290Expression and activation of either PPARG 1 or 2 reduced de novo lipogenesis and oxidative stress and mediated a switch from glucose to fatty acid oxidation through regulation of genes including Pdk4, Fabp4, Lpl, Acot1 and Cd36. A PPARG agonist versus high-fat diet (HFD) regimen in vivo confirmed that PPARG agonization increased prostatic differentiation markers, whereas HFD downregulated PPARG-regulated genes and decreased prostate differentiation.https://www.nature.com/articles/cddis201299Senescent cells in benign prostate hyperplasia (BPH) tissue induce a senescence-associated secretory phenotype (SASP) which, by generating inflamed microenvironment and reactive stroma, promotes leukocyte infiltration, cellular hyperproliferation, and nodular prostate growth.
SASP induced mRNA expression for inflammatory cytokines (IL-1a, IL-6, IL-8, TNF-a); chemokines (GM-CSF, CXCL12); metalloproteases (MMP-1, MMP-3, MMP-10); growth factor binding IGFBP-3.
Senescent cells are metabolically active, but irreversibly arrested at the G1/S cell cycle check point. As a cell-intrinsic tumor-suppressive mechanism, cellular senescence bars aberrant proliferation of cells that are irreversibly damaged by insults such as oxidative stress induced by cell's metabolic activities, chromosomal instability from shortened telomeres, and DNA damage by chemicals or ionizing radiation. Elevated expression of the p16INK4a/CDKN2a tumor suppressor is associated with cellular senescence in many tissues. Senescence-associated beta-galactosidase (SA-BGal) activity at pH 6.0 is another marker for senescent cells. Cells of the BPH epithelium and late-passage epithelial cells isolated from the normal prostate transition zone showed elevated p16/INK4a and SA-BGal.
BPH-1 cells, showed increased AKT and ERK activities. The prevailing view on BPH pathogenesis is that the cumulative effects of low-level chronic stimulation of prostate cells by inflammatory secretions from the reactive stroma and infiltrated inflammatory cells promote excessive cell proliferation in aging prostate. AKT promotes cell growth and proliferation by activating mTORC1 and downstream effectors that stimulate protein synthesis and lipogenesis.https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fba.2018-00084Please take notice that both 3a-Adiol and 3B-adiol are 5alpha metabolites.
As the metabolic clearance rate decreases in male senescence, the net result is an important decrease in the testosterone blood production rate. It was observed that testosterone metabolism in male senescence is characterized by a relative decrease of the formation of androstanediols, with a relative increase of 5beta over 5alpha metabolites; moreover a statistically significant correlation between the formation of 3a-Adiol and the free testosterone fraction was found.https://academic.oup.com/jcem/article-abstract/34/4/730/2685686The 5a-androstanediol analyte contains both the 3a-adiol and 3B-adiol subcomponents.https://lmreview.com/bio-identical-hormone-replacement-selecting-the-right-hormone-tests-for-your-male-patient/Age is associated with a decrease in 3a-diol production and 3a-diol administration reinstates cognitive and affective performance of aged male rats. 3a-diol has actions at GABAA receptors or at estrogen receptor beta in the hippocampus.https://www.frontiersin.org/articles/10.3389/fnagi.2010.00015/fullThe present study demonstrated that SIRT1 activation attenuated HFD-induced liver steatosis and inflammation by inhibiting CD36 expression and the NF-kB signaling pathway.
In addition, another study reported that SIRT1 expression was decreased in aged mice, whereas CD36 was upregulated, which could explain the increasing prevalence and progression of NAFLD associated with age in the general human population. The AMPK-mediated effects of SIRT1 have been reported to promote the deacetylation of PGC-1a, which then stimulates PPARA, leading to the initiation of CD36 transcription.
Studies have shown that CD36 contributes to the development of NAFLD by modulating the rate of free fatty acid uptake. Some researchers regard CD36 as a protective metabolic sensor in the liver during lipid overload or metabolic stress.https://www.spandidos-publications.com/mmr/18/2/1609LPS impairs steroidogenesis and ROS metabolism and induces PPAR transcriptional activity to disturb estrogen/androgen receptor expression in testicular cells. Inflammation can deregulate the testicular functions of steroidogenesis and spermatogenesis, consequently contributing to male infertility.
Our results suggested PPARA/PPARG mRNA was highly expressed in late spermatids, while PPARB mRNA was highly expressed in round spermatids.
PPARG were upregulated in primary Sertoli cells after LPS-treatment.
In MLTC1 cells and ERB mRNA in TM4 cells were significantly recovered after treatment with the specific PPARG-antagonist GW9662.
Meanwhile, PPARs (PPARA and PPARG) can interact with G-coupled membrane estrogen receptor to regulate the steroidogenic function of mouse Leydig cells.
The silent information regulator type 1 (SIRT1) protein, a deacetylase that catalyzes deacetylation reactions in an NAD+-dependent manner, can inhibit PPAR activation. Moreover, Sirt1 transcription is inhibited through a negative feedback loop by PPARG, which binds to promoter region of the Sirt1 gene to suppress its transcription.
PPARA was mainly localized in the nuclear regions of Leydig cells and that PPARG was mainly detected in Sertoli cells.
Sirtuins play a key role in many vital processes of cells. including the cellular oxidative stress response and energy metabolism. SIRT1, a member of the Sirtuin family, is a deacetylase that catalyzes deacetylation reactions in an NAD+-dependent manner to inhibit PPAR activation. Meanwhile, the transcription of the SIRT1 deacetylase gene is inhibited via a negative feedback loop by PPARG. PPARG can bind to the promoter region of the Sirt1 gene to inhibit Sirt1 expression at the transcriptional level. Moreover, the SIRT1 protein can also bind the Sirt1 promoter, resulting in the repression of the Sirt1 gene. Most Sirtuin mRNAs, except Sirt4, were expressed in spermatids.
Our results revealed that PparA and PparG mRNA expression was strongly increased after
LPS treatment. This decreased SIRT1 expression may have been caused by the upregulated PPARG protein abundance, as PPARG can bind to the Sirt1 promoter region to repress its gene expression via a negative feedback loop. In conclusion, the SIRT1- PPARG regulation loop may play a very important role in the primary mouse Sertoli cell model of LPS infection.
The molecular role of reactive oxygen species (ROS) is essential for male spermatogenesis and steroidogenesis.
The estrogen/androgen balance plays an important role in the maintenance of normal testicular morphology and spermatogenesis. After LPS treatment, ERB expression was strongly increased in TM4 Sertoli cells; in contrast, AR mRNA expression was decreased.
Taken together, our results suggest that LPS impairs steroidogenesis and ROS metabolism and induces PPAR transcriptional activity to disturb estrogen/androgen receptor expression in testicular cells.https://sci-hub.se/https://link.springer.com/article/10.1007/s11033-019-05196-6On macrophages CD36 forms part of a non-opsonic receptor and is involved in phagocytosis. CD36 has also been implicated in hemostasis, thrombosis, malaria, inflammation, lipid metabolism and atherogenesis. CD36 ligands have also been shown to promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Recently, CD36 was linked to store-operated calcium flux, phospholipase A2 activation, and production of prostaglandin E2. Recent researches concluded that the CD36 is involved in the fat taste transduction (olegustus).
Upregulation of CD36 could contribute to membrane remodeling during senescence. In response to various senescence-inducing stimuli, CD36 stimulate NF-kB-dependent inflammatory cytokine and chemokine production, a phenomenon known as SASP. This secretory molecule production leads to the onset of a comprehensive senescent cell fate.https://en.wikipedia.org/wiki/CD36CD36 serves as a signaling hub protein at the crossroad of inflammation, lipid metabolism, and fatty acid metabolism. In addition, the level of soluble CD36 (unattached to cells) in the circulating blood was elevated in patients with atherosclerosis and other metabolic disorders.
CD36, a major class B scavenger receptor, exerts substantial effects on ox-LDL uptake by macrophages. Cumulative data have indicated the important role of CD36 in regulating key physiological processes and cellular events in the initial and progression phases of atherosclerosis, such as inflammation, lipid metabolism, endothelial dysfunction, smooth muscle cell dysfunction, and foam cell formation.
PPARG represents a primary transcription factor that binds to the promoter region of CD36 and modulates CD36 in a positive feedback manner.
STAT5 activated PPARG through inhibition of CD36. Pregnane X receptor (PXR) increased CD36 expression concomitant with lipid accumulation in macrophages.
In fact, the interaction between miRNA and CD36 is closely associated with lipid metabolic disorders.
The CD36 SNPs variants were associated with CD36 expression due to the methylation of CD36, indicating that SNPs and methylation appear to regulate CD36 mRNA expression.
Autophagy modulates cholesterol mobilization from macrophage to reverse cholesterol transport, which is deregulated in advanced atherosclerosis. Importantly, CD36 expression was also decreased due to the activation of autophagy upon empagliflozin treatment.
The ingestion of ox-LDL was inhibited by ubiquitin-proteasome system via promoting CD36 degradation. CD36 can transduce src family non-receptor tyrosine kinases, JNK, ERK 1/2, IRGM1 and TLR2/6-dependent signaling.
Interestingly, increased CD36 expression leads to mitochondrial ROS overproduction in aortic lesion macrophages upon stimulation of pro-atherogenic ox-LDL, which could switch the mitochondrial metabolism to superoxide production. However, inhibition of mitochondria-derived superoxide generation suppresses ox-LDL induced NF-kB activation and pro-inflammatory cytokine production. These findings suggest the therapeutic possibility to treat chronic inflammation and atherosclerosis by targeting oxidized LDL/CD36 signaling in macrophages via modulating dysregulated fatty acid metabolism and mitochondria ROS production.
CD36 expression was increased upon simulation with ox-LDL or high-fat diet feeding, which promoted aortic uptake of oxLDL or other modified lipids.
CD36 can take up FAs through enhancing the rate of intracellular esterification.
Ox-LDL can induce CD36 expression though PPARG, which in turn promotes ox-LDL uptake by the macrophages and entrapment of macrophages within the plaques, allowing for macrophages to become lipid-laden foam cells.
Testicular orphan nuclear receptor 4 (TR4) can sensor the increased generation of FA and promote the expression of CD36, which forms a vicious cycle that finally contributes to the formation of foam cells.
Pharmacological Modifiers of CD36
Statins, the most widely used lipid-lowering drugs, can inhibit CD36 expression/activity via a PPARG-dependent pathway in macrophages. Statins (fluvastatin and pitavastatin) also decreased CD36 expression in aortic VSMCs. Nifedipine, also suppressed CD36 expression and lipid uptake and deposition in macrophages. Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, decreased CD36 expression. Tamoxifen, an anti-breast cancer medicine also decreased CD36-dependent foam cell formation. Andrographolide inhibited CD36 level. Pomegranate peel polyphenols, spiromastixones, and puerarin could suppress CD36 expression. Tanshinone IIA from Danshen, prevented atherothrombosis by targeting platelet CD36. Orientin, a flavonoid from plants, quercetin and curcumin.
CD36 acts a multi-functional inflammatory-metabolic receptor by physiologically regulating lipid homeostasis and immune homeostasis.https://sci-hub.se/https://link.springer.com/article/10.1007/s11883-020-00870-8Aging decreases Nrf2. Nrf2-/- mice displayed a significant reduction in the Serca2a expression below the baseline.https://www.frontiersin.org/articles/10.3389/fphys.2017.00268/fullNrf2 remains low under normal conditions but it is induced many-fold in response to endogenous or exogenous stresses or toxicants. Nrf2 target genes function in elimination of reactive oxygen species (ROS) and diminishing inflammation, drug and carcinogen detoxication, and intermediary metabolism.
Autophagy in cancer cells may have bimodal response of pro-death or a pro-survival role. Lower rate of autophagy may result in catabolic degradation of nonessential cellular proteins and debris creating a large amino acid pool that eventually helps in cancer cell survival. In contrary, uncontrolled autophagy mimicking to apoptotic cell death results in large scale tumor cell death. Hence, autophagy can either promote or suppress the survival and proliferation in the tumor microenvironment.https://cancerci.biomedcentral.com/articles/10.1186/s12935-020-1153-yActivator protein 1 (AP-1) subunit c-Jun can dimerize with NRF2 and activate NRF2-induced transcription, while another AP-1 subunit c-Fos can suppress NRF2-induced transcription.
Nuclear receptors PPARG and estrogen receptor alpha (ERa) can directly bind to NRF2 and suppress the NRF2 activity.
Transient NRF2 activation as a stress response mediates the cellular programs trying to maintain the homeostasis if the damage caused by the toxic stimuli are reparable. NRF2 upregulates expression of genes involved in the glycolysis, glycogen metabolism, pentose phosphate pathway, one carbon metabolism, amino acid metabolism, nucleotide biosynthesis, glutaminolysis, fatty acid synthesis, heme metabolism, and glutathione synthesis and utilization. NRF2 downregulates the expression of genes involved in the gluconeogenesis.
In addition, NRF2 also activates CD36, the lipid uptake transporter/receptor in different cells to regulate lipid metabolism.
Misfolded protein accumulation and aggregation induce excessive production of ROS from mitochondria, ER, and other sources, which can activate NRF2. NRF2 is a hub that compiles emergency signals derived from misfolded protein accumulation to facilitate a coordinated transcriptional response.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369905/Elevated free fatty acid (FFA) uptake via CD36 promotes epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). The Wnt and TGF-B signaling pathways were activated upon FFA treatment, potentially acting as upstream activators of the EMT program. We observed that Wnt and TGF-B signaling pathways were activated by palmitate and there could be several mechanisms involved. Oncogenic transcription factors, including NF-kB, AP-1 and STAT3, activated by inflammatory cytokines like TNF-a and IL-6 could connect the activation of Wnt and TGF-B signaling pathways with elevated FFA. The STAT3 transcription factor was shown to mediate the induction of EMT. A different mechanism of EMT induction could be the activation of the unfolded protein response or ER-stress pathway by FFA. CD36 crosstalk with TLR2/6 heterodimer results in activation of TLR-dependent cytokine production (NF-kB). In the context of EMT, the relationships of these pro-inflammatory pathways with CD36 point to a possibility that FFA may activate EMT via CD36 signaling.https://www.nature.com/articles/srep14752Signal transducer and activator of transcription (STAT) proteins are a family of transcription factors that mediate gene expression in response to cytokines and growth factors. STAT3 regulates a variety of genes involved in cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, inflammation, and immunity.https://www.researchgate.net/profile/Jose-Luis-40/publication/343413659_Virtual_Screening_of_Natural_Products_Database/links/5f32af99458515b72916922f/Virtual-Screening-of-Natural-Products-Database.pdfSilencing CD36 gene expression results in the inhibition of latent-TGF-B1 activation and suppression of silica-induced lung fibrosis in the rat.https://respiratory-research.biomedcentral.com/articles/10.1186/1465-9921-10-36TGF-B1/TGF-B2 down-regulated CD36 expression by inactivating PPARG-mediated signaling. Our data demonstrate for the first time that TGF-B1 and TGF-B2 decrease expression of CD36 by a mechanism involving phosphorylation of MAP kinase, subsequent MAP kinase phosphorylation of PPARG, and a decrease in CD36 gene transcription by phosphorylated PPARG.https://www.jbc.org/article/S0021-9258(18)31241-9/fulltextIt has been known for decades that an increased provision of lipids to a working muscle (such as during exercise) promotes fatty acid oxidation (FAO). We have provided evidence that fatty acid translocase (FAT)/CD36 is a key regulator of lipid transport across both the sarcolemmal and mitochondrial membranes and, therefore, rates of skeletal muscle fatty acid oxidation.
Exercise-induced signaling cascades (potentially including calcium, ERK1/2, PKC, and AMPK) promote the translocation of intracellular stores of FAT/CD36 to both the sarcolemma and the mitochondria.
This acute redistribution of FAT/CD36 to the plasma membrane in response to exercise is hypothesized to be regulated, in part, by calcium-mediated signaling events as fatty acid transport is increased when muscle is exposed to caffeine (a cytosolic calcium level enhancer), and this increase in fatty acid transport occurs concomitantly with an increase in plasma membrane FAT/CD36. In addition, fatty acid transport is attenuated when muscles are exposed to inhibitors for calcium signaling (CaMKII and CaMKK), and this corresponds to a prevention of FAT/CD36 translocation to the plasma membrane.
The role of AMPK in regulating sarcolemmal FAT/CD36 translocation during exercise remains unclear. Inhibition of extracellular signaling receptor kinase (ERK1/2) seems to prevent contraction-induced FAT/CD36 translocation and activation of protein kinase C (PKC) in cardiac myocytes induces FAT/CD36 translocation.
In mature rodent muscle, overexpression of PGC-1a (a well-characterized exercise adaptation regulator) increases mitochondrial FAT/CD36 expression in concert with increasing FAO. The presence of FAT/CD36 on the sarcolemmal and/or the mitochondrial membrane can effectively enhance and promote fatty acid transport/oxidation with an increase in fatty acid provision.https://journals.lww.com/acsm-essr/FullText/2012/10000/A_Dual_Mechanism_of_Action_for_Skeletal_Muscle.5.aspxThe transcription factor STAT 6 accumulates in response to IL-4 and, along with its downstream effector PPARG, has a central role in the regulation of transcription of anti-inflammatory and pro-resolving genes. Additionally, IL-4 induces expression of CD36, a receptor of lipoproteins, whose uptake and metabolism may support fatty-acid oxidation, contributing to metabolic microglia reprogramming.https://onlinelibrary.wiley.com/doi/full/10.1002/glia.23484The entrance of SARS-CoV-2 using ACE2 receptor triggers an array of multiple molecular signaling beyond that of the angiotensin II/ACE2-Ang-(1–7) axis, such as down-regulation of PGC-1a/irisin, increased SREBP-1c activity, upregulation of CD36 and Sirt1 inhibition leading to insulin resistance.
TLR4, as an important component of the immune system, has direct interaction with CD36 in macrophages and monocytes. TLR4-induced up-regulation of CD36.
Angiotensin II resulted in indirect increased expression of CD36 through down-regulation of sirtuin 1.
The entrance of SARS-CoV-2 using ACE2 receptor triggers an array of multiple molecular signaling beyond that of the angiotensin II/ACE2-Ang-(1–7) axis such as down-regulation of PGC-1a/irisin, increased SREBP-1c activity, upregulation of CD36 and Sirt1 inhibition leading to insulin resistance.https://link.springer.com/article/10.1007/s11033-021-07109-yAll genes (PPARG, CD36, STAB1, ITGAV, and ANXA2) downregulated in surviving patients with COVID-19 are related to cholesterol homeostasis. We hypothesized that upregulation of CD36 expression could be a predictive factor for severe COVID-19 with possible lethal outcomes.
PPARG bridges the lipid microenvironment and immune cell’s function driving its differentiation and functional phenotypes. PPARG has an immunomodulatory function and plays a role in the resolution of inflammation, its upregulation in nonsurvivors may be a hallmark of nonresolved inflammation in condition of lipid depletion which is characteristic of severe COVID-19.https://www.mdpi.com/2073-4409/10/12/3495CD36 has been previously shown to be an important mediator of acute lung injury in animal models exposed to hydrogen peroxide or infected with malaria. Our results suggest that CD36 receptors may be implicated in the pathogenesis of severe infection in critically ill patients with COVID-19. sCD36 could be a potential biomarker for severe illness outcomes, and test novel anti-CD36 therapeutics in ARDS.https://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2022.205.1_MeetingAbstracts.A1284In addition to the regulation of mitochondrial function, PGC-1a increases mRNA content of enzymes involved in fat metabolism such as fatty-acid translocase/CD36, carnitine palmitoyltransferase I, and medium-chain acyl-coenzyme A dehydrogenase (MCAD) in skeletal muscle.https://academic.oup.com/abbs/article/43/4/248/884?login=truePGC-1a is also known to activate factors, e.g., PPARs, that increase the cellular and organelle uptake, and the catabolic oxidation, of fatty acids (FAO). This effect was reflected by a 3.5-fold increased expression in MCK-PGC-1a mouse muscle of CD36/FAT, a gene encoding the plasma membrane transporter of fatty acids. The expression of the FAO-related CD36/FAT gene was significantly increased in all treated groups. https://www.sciencedirect.com/science/article/pii/S1550413111002117COX-2 is regulated by a negative feedback loop mediated through PPARG, which makes possible a dynamic production of PG, especially in macrophages, and may be attributed to various expression patterns and physiological functions of COX-2.https://sci-hub.se/https://www.tandfonline.com/doi/abs/10.1517/13543776.2013.834888Expression of ERB is found reduced in tumour tissue and inversely related to mortality. Epigenome-wide DNA methylation profiling was performed. Comparing tumours of high with tumours of negative ERB expression revealed 2,904 differentially methylated CpG sites of which 403 were replicated. Replicated CpGs were annotated to genes such as CD36, HK1 or LRP5.https://www.tandfonline.com/doi/full/10.1080/15592294.2019.1595998Genes involved in spermatogenesis (TSSK2, HSP90AA1, SOX5, SPAG16, and SPATC1) were up-regulated in male macaques, and significant changes in genes (CD36), metabolites (cholesterol, 7- ketolithocholic acid, and 12-ketolithocholic acid), and microbiota (Lactobacillus) related to cholesterol metabolism were also found, suggesting the sexually mature males have stronger sperm fertility and cholesterol metabolism compared to sexually immature males.
In macaques, cholesterol is a recognized regulator of male fertility and cholesterol homeostasis is essential for sperm maturation. Here, the expression of CD36, which is associated with cholesterol transport, was decreased in the sexually mature male group. Endogenous CD36 mediates the endocytosis of native low-density lipoproteins (LDLs), which is required for cholesterol transfer. High intracellular cholesterol can reduce cholesterol uptake by inhibiting the expression of LDL receptor genes. Decreased CD36 expression may lead to elevated plasma cholesterol, suggesting that male macaques have sufficient cholesterol for the synthesis of various steroids in sex organs after sexual maturity.https://assets.researchsquare.com/files/rs-2229246/v1/ee4313ff-53e4-44fb-8447-66b357e09d65.pdf?c=1668543014Such a study revealed that with respect to control cells, the PPARG knock-out cells exhibited significant reduction in the expression of genes coding for PPARA, CD-36, LDL-R as well as significant increase in the expression of genes coding for IL-4, IL-8, IFN-g, CX3CR1, hTERT.https://link.springer.com/article/10.1007/s11010-006-9169-8Most studies on cellular senescence (CS) have been conducted in vitro on normal and tumor cell lines. These different approaches lead to DNA damage, gene instability, telomerase inhibition, and/or chromatin alterations that primarily affect p53 - p21 signaling.
We found that senescent cells were mostly detected in hyperplastic and premalignant lesions and rarely in tumors. In MNU-mammary carcinogenesis model, tamoxifen, vorazole (an aromatase inhibitor), DHEA, retinoids [all-trans retinoic acid (atRA), 9-cis-retinoic acid (9cRA), 4-hydroxyphenyl-retinamide (4-HPR) and rexinoids (LDG1069), in addition to inhibition of cell proliferation also induced cellular senescence. Cellular senescence induced by tamoxifen, DHEA, aromatase inhibitors and rexinoids was associated with p21 and p16 up-regulation and with decrease in telomerase activity.https://aacrjournals.org/mcr/article-split/11/10_Supplement/A122/234606/Abstract-A122-Role-of-cellular-senescence-inAlthough PPARA has been linked to hepatocarcinogenesis in rodents, several epidemiological studies suggest that this is unlikely to be observed in humans. Similarly, although PPARG activation has often been linked to proliferation inhibition and apoptosis induction in cancer cells, various studies have yielded contradictory results that suggest PPARG activation may promote cancer development.https://www.tandfonline.com/doi/pdf/10.2147/BCTT.S316667
