scholarly journals Selective Ah Receptor Ligands Mediate Enhanced SREBP1 Proteolysis to Restrict Lipogenesis in Sebocytes

2019 ◽  
Vol 171 (1) ◽  
pp. 146-158 ◽  
Author(s):  
Gulsum E Muku ◽  
Nicholas Blazanin ◽  
Fangcong Dong ◽  
Philip B Smith ◽  
Diane Thiboutot ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Acne Vulgaris ◽  
Lipid Synthesis ◽  
Inverse Correlation ◽  
Acid Synthesis ◽  
Ah Receptor ◽  
Sebaceous Glands ◽  
Lipogenic Genes ◽  
Aryl Hydrocarbon

Abstract The aryl hydrocarbon receptor (AHR) mediates 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity that can lead to chloracne in humans. A characteristic of chloracne, in contrast to acne vulgaris, is shrinkage or loss of sebaceous glands. Acne vulgaris, on the other hand, is often accompanied by excessive sebum production. Here, we examined the role of AHR in lipid synthesis in human sebocytes using distinct classes of AHR ligands. Modulation of AHR activity attenuated the expression of lipogenic genes and key proinflammatory markers in the absence of canonical DRE-driven transcription of the AHR target gene CYP1A1. Furthermore, topical treatment with TCDD, which mediates DRE-dependent activity, and SGA360, which fails to induce DRE-mediated responses, both exhibited a decrease in the size of sebaceous glands and the number of sebocytes within each gland in the skin. To elucidate the mechanism of AHR-mediated repression of lipid synthesis, we demonstrated that selective AHR modulators, SGA360 and SGA315 increased the protein turnover of the mature sterol regulatory element-binding protein (mSREBP-1), the principal transcriptional regulator of the fatty acid synthesis pathway. Interestingly, selective AHR ligand treatment significantly activated the AMPK-dependent kinase (AMPK) in sebocytes. Moreover, we demonstrated an inverse correlation between the active AMPK and the mSREBP-1 protein, which is consistent with the previously reported role of AMPK in inhibiting cleavage of SREBP-1. Overall, our findings indicate a DRE-independent function of selective AHR ligands in modulating lipid synthesis in human sebocytes, which might raise the possibility of using AHR as a therapeutic target for treatment of acne.

scholarly journals How Ah Receptor Ligand Specificity Became Important in Understanding Its Physiological Function

2020 ◽  
Vol 21 (24) ◽  
pp. 9614
Author(s):  
Iain A. Murray ◽  
Gary H. Perdew
Keyword(s):  
Physiological Function ◽  
Innate Immune ◽  
Ah Receptor ◽  
Ligand Specificity ◽  
Aryl Hydrocarbon ◽  
Innate Immune Signaling ◽  
Tryptophan Metabolites ◽  
Barrier Tissues ◽  
Endogenous Metabolites

Increasingly, the aryl hydrocarbon receptor (AHR) is being recognized as a sensor for endogenous and pseudo-endogenous metabolites, and in particular microbiota and host generated tryptophan metabolites. One proposed explanation for this is the role of the AHR in innate immune signaling within barrier tissues in response to the presence of microorganisms. A number of cytokine/chemokine genes exhibit a combinatorial increase in transcription upon toll-like receptors and AHR activation, supporting this concept. The AHR also plays a role in the enhanced differentiation of intestinal and dermal epithelium leading to improved barrier function. Importantly, from an evolutionary perspective many of these tryptophan metabolites exhibit greater activation potential for the human AHR when compared to the rodent AHR. These observations underscore the importance of the AHR in barrier tissues and may lead to pharmacologic therapeutic intervention.

Molecular regulation of SREBP function: the Insig-SCAP connection and isoform-specific modulation of lipid synthesis

2004 ◽  
Vol 82 (1) ◽  
pp. 201-211 ◽  
Author(s):  
Ruth McPherson ◽  
Andre Gauthier
Keyword(s):  
Acid Metabolism ◽  
Regulatory Element ◽  
Lipid Synthesis ◽  
Molecular Regulation ◽  
New Information ◽  
Ubiquitin Proteasome ◽  
Sterol Regulatory Element ◽  
Membrane Bound ◽  
Proteasome Pathway

Sterol regulatory element binding proteins (SREBPs) are a family of membrane-bound transcription factors that play a unique and fundamental role in both cholesterol and fatty acid metabolism, relevant to human disease. There are three SREBPs that regulate the expression of over 30 genes. SREBPs are subject to regulation at three levels: proteolytic cleavage, rapid degradation by the ubiquitin-proteasome pathway, and sumoylation. Recently, there have been exciting advances in our understanding of the molecular mechanism of SREBP trafficking and processing with new information on the role of insulin-induced genes and the differential role and regulation of SREBP-1c and -2, which may ultimately lead to novel strategies for the treatment of dyslipidemia and insulin resistance.Key words: SREBP, Insig, SCAP, cholesterol synthesis, lipid metabolism.

scholarly journals The effect of dietary docosahexaenoic acid on the expression of lipogenic genes in broilers

2007 ◽  
Vol 58 (2) ◽  
pp. 153 ◽  
Author(s):  
H. J. Chin ◽  
Y. H. Ko ◽  
T. F. Shen ◽  
S. T. Ding
Keyword(s):  
Fatty Acid ◽  
Docosahexaenoic Acid ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Regulatory Element ◽  
Acid Synthesis ◽  
Daily Weight Gain ◽  
Feed Conversion ◽  
Lipogenic Genes ◽  
Triacylglycerol Synthesis

The objectives of this work were to determine the effects of dietary fungal docosahexaenoic acid (DHA) on tissue DHA concentration and lipogenic gene expression in broilers. A fungal (SR-21) meal product containing 31.5% total fat and 32.7% DHA (% of total fatty acids) was fed to chicken broilers at 0, 1, or 3% for 3 weeks. A diet with 1% DHA oil (containing 40% DHA) was also fed to chicken broilers as a positive control. Dietary fungal meal supplementation (3%) improved daily weight gain, food intake, and feed conversion ratio. The fungal meal supplementation increased dietary DHA content and consequently increased the DHA content in plasma, breast muscle (Pectoralis major), and livers in the broilers. The plasma triacylglycerol concentration was decreased by the supplementation of dietary DHA. The data indicate that the dietary DHA treatment modified certain aspects of the lipid metabolism, especially pathways related to triacylglycerol synthesis. Indeed, both the 1% DHA oil and 3% fungal meal treatments decreased the hepatic lipogenic transcription factor sterol regulatory element binding protein 1 (SREBP1) mRNA relative abundance, suggesting that dietary DHA supplementation decreases SREBP1 gene functions. The relative mRNA abundance of the de novo fatty acid synthesis genes, fatty acid synthase and acetyl coenzyme A carboxylase, was reduced by 1% DHA oil and 3% fungal meal treatments, suggesting that dietary DHA supplementation decreases lipogenesis in the livers of the broilers. Taken together, the fungal meal is a suitable dietary supplement to increase tissue DHA content and reduce the expression of hepatic lipogenic genes in broilers.

scholarly journals The Role of Mitochondrial Fat Oxidation in Cancer Cell Proliferation and Survival

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2600
Author(s):  
Matheus Pinto De Oliveira ◽  
Marc Liesa
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Cancer Proliferation

Tumors remodel their metabolism to support anabolic processes needed for replication, as well as to survive nutrient scarcity and oxidative stress imposed by their changing environment. In most healthy tissues, the shift from anabolism to catabolism results in decreased glycolysis and elevated fatty acid oxidation (FAO). This change in the nutrient selected for oxidation is regulated by the glucose-fatty acid cycle, also known as the Randle cycle. Briefly, this cycle consists of a decrease in glycolysis caused by increased mitochondrial FAO in muscle as a result of elevated extracellular fatty acid availability. Closing the cycle, increased glycolysis in response to elevated extracellular glucose availability causes a decrease in mitochondrial FAO. This competition between glycolysis and FAO and its relationship with anabolism and catabolism is conserved in some cancers. Accordingly, decreasing glycolysis to lactate, even by diverting pyruvate to mitochondria, can stop proliferation. Moreover, colorectal cancer cells can effectively shift to FAO to survive both glucose restriction and increases in oxidative stress at the expense of decreasing anabolism. However, a subset of B-cell lymphomas and other cancers require a concurrent increase in mitochondrial FAO and glycolysis to support anabolism and proliferation, thus escaping the competing nature of the Randle cycle. How mitochondria are remodeled in these FAO-dependent lymphomas to preferably oxidize fat, while concurrently sustaining high glycolysis and increasing de novo fatty acid synthesis is unclear. Here, we review studies focusing on the role of mitochondrial FAO and mitochondrial-driven lipid synthesis in cancer proliferation and survival, specifically in colorectal cancer and lymphomas. We conclude that a specific metabolic liability of these FAO-dependent cancers could be a unique remodeling of mitochondrial function that licenses elevated FAO concurrent to high glycolysis and fatty acid synthesis. In addition, blocking this mitochondrial remodeling could selectively stop growth of tumors that shifted to mitochondrial FAO to survive oxidative stress and nutrient scarcity.

scholarly journals Endocrine Disrupting Chemicals, Hormone Receptors, and Acne Vulgaris: A Connecting Hypothesis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1439
Author(s):  
Akshatha Rao ◽  
Sotonye C. Douglas ◽  
Julianne M. Hall
Keyword(s):  
Hormone Receptors ◽  
Acne Vulgaris ◽  
Endocrine Disrupting Chemicals ◽  
Protective Role ◽  
Receptor Ligands ◽  
Lipogenic Genes ◽  
Skin Cells ◽  
Endocrine Disrupting ◽  
The Relationship

The relationship between endocrine disrupting chemicals (EDCs) and the pathogenesis of acne vulgaris has yet to be explored in the literature. Acne vulgaris is a chronic inflammatory skin disease of the pilosebaceous unit. The pathogenesis of acne involves several hormonal pathways, including androgens, insulin-like growth factor 1(IGF-1), estrogens, and corticosteroids. EDCs influence these pathways primarily through two mechanisms: altering endogenous hormone levels and interfering with hormone receptor function. This review article describes the mechanistic links between EDCs and the development of acne lesions. Highlighted is the contributory role of androgen receptor ligands, such as bisphenol A (BPA) and mono-2-ethylhexyl Phthalate (MEHP), via upregulation of lipogenic genes and resultant exacerbation of cholesterol synthesis. Additionally discussed is the protective role of phytoestrogen EDCs in counteracting androgen-induced sebocyte maturation through attenuation of PPARy transcriptional activity (i.e., resveratrol) and restoration of estrogen-regulated TGF-B expression in skin cells (i.e., genistein). Examination of the relationship between EDCs and acne vulgaris may inform adjunctive avenues of treatment such as limiting environmental exposures, and increasing low-glycemic, plant-rich foods in the diet. With a better understanding of the cumulative role that EDCs play in acne, clinicians can be better equipped to treat and ultimately improve the lives of their patients.

scholarly journals Recent insight into the correlation of SREBP-mediated lipid metabolism and innate immune response

2018 ◽  
Vol 61 (3) ◽  
pp. R123-R131 ◽  
Author(s):  
Hyeon Young Park ◽  
Hye Suk Kang ◽  
Seung-Soon Im
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Regulatory Element ◽  
Acid Synthesis ◽  
Metabolic Intermediates ◽  
Sterol Regulatory Element ◽  
Insight Into

Fatty acids are essential nutrients that contribute to several intracellular functions. Fatty acid synthesis and oxidation are known to be regulated by sterol regulatory element-binding proteins (SREBPs), which play a pivotal role in the regulation of cellular triglyceride synthesis and cholesterol biogenesis. Recent studies point to a multifunctional role of SREBPs in the pathogenesis of metabolic diseases, such as obesity, type II diabetes and cancer as well as in immune responses. Notably, fatty acid metabolic intermediates are involved in energy homeostasis and pathophysiological conditions. In particular, intracellular fatty acid metabolism affects an inflammatory response, thereby influencing metabolic diseases. The objective of this review is to summarize the recent advances in our understanding of the dual role of SREBPs in both lipid metabolism and inflammation-mediated metabolic diseases.

scholarly journals Evaluating the Role of Aryl Hydrocarbon Receptors in Acne Vulgaris Patients

2020 ◽  
Vol 5 (6) ◽  
pp. 1-6
Author(s):  
F.M. El-Esawy ◽  
S.A. Mohamed ◽  
D.M. Elhabak ◽  
E.N. Nasar
Keyword(s):  
Acne Vulgaris ◽  
Aryl Hydrocarbon Receptors ◽  
Aryl Hydrocarbon

scholarly journals Assessment of efficacy and safety of dapsone gel 5% in the treatment of acne vulgaris

2019 ◽  
Vol 15 (1) ◽  
pp. 136-162
Author(s):  
Yasir Mansour Al-Ani
Keyword(s):  
Propionibacterium Acnes ◽  
Skin Diseases ◽  
Acne Vulgaris ◽  
Innate Immune ◽  
Matrix Remodeling ◽  
Sebaceous Glands ◽  
Social Ostracism ◽  
Recent Laboratory

ABSTRACTBackground : Acne vulgaris is acommon skin disease, affecting more than 85% ofadolescents and often continuing into adulthood.People between 11 and 30 years of age and up to5% of older adults. For most patients acne remainsa nuisance with occasional flares of unsightlycomedones, pustules and nodules. For other lessfortunate persons, the sever inflammatory responseto Propionibacterium acnes (P.acnes) results inpermanentMethods: Disfiguring scars. (1, 2) Stigmata of severacne cane lead to social ostracism, withdrawalfrom society and severe psychologicdepression (1-4).Result Pathogenesis of acne Traditionally, acnehas been thought of as a multifactorial disease ofthe folliculosebaceous unit, involving excesssebum production, abnormal follicularhyperkeratinization, overgrowth ofPropionibacterium acnes, and inflammation (Fig2). Recent laboratory and clinical investigationsinto the roles of the innate immune system andextracellular matrix remodeling proteins have shedadditional light on this pathogenetic process (5-7).Role of androgens: Activity of type 1 5areductaseenzyme was shown to predominate inhuman sebaceous glands and epidermis. Thisenzyme is responsible for the conversion oftestosterone to the more potent androgen,dihydrotestosterone (DHT). DHT in turn is thoughtto mediate androgen dependent skin diseases suchas acne, hirsutism and androgenetic alopecia (13)The enzyme 5a-reductase type 1 has been studiedin those with and without acne and it has beenhypothesized that those with acne might have moreactive 5a-reductase type 1 .(2)Conclusion : The prominent role of hormones inthe pathophysiology of acne has long beenrecognized and corroborated by clinical andexperimental observations and therapeuticexperience (14). Although acne is not considered aprimary endocrine disorder, androgens, such asdihydrotestosterone, dehydroepiandrosteronesulfate, and testosterone, and growth hormone andinsulin-like growth factors, have all beenimplicated in the pathogenesis of acne (15).Corresponding address to :Dr. Yasir Mansour Mohamed Al-AniIslam Mohammad Nabil El Helou

scholarly journals 6-Shogaol Antagonizes the Adipocyte-Conditioned Medium-Initiated 5-Fluorouracil Resistance in Human Colorectal Cancer Cells through Controlling the SREBP-1 Level

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1067
Author(s):  
Ko-Chao Lee ◽  
Kuen-Lin Wu ◽  
Chia-Kung Yen ◽  
Cheng-Nan Chen ◽  
Shun-Fu Chang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Conditioned Medium ◽  
Regulatory Element ◽  
Combined Therapy ◽  
Lipid Synthesis ◽  
Resistance Development ◽  
Ampk Signaling ◽  
Element Binding Protein ◽  
Clinical Drugs

The resistance of colorectal cancer (CRC) to chemotherapy, e.g., 5-fluorouracil (5-FU), is an impediment to successful cancer treatment. Although many mechanisms have been proposed to explain the occurrence of resistance, little is known concerning the role of the adipocyte-containing microenvironment of CRC. Accumulating data have proposed that the combined therapy of clinical drugs with ginger derivatives, e.g., 6-shogaol, might improve resistance development. In the present study, we examined the effect of adipocyte-conditioned medium (ACM) on 5-FU-treated CRC cells (human DLD-1 and SW480 cells) and further examined the possible antagonized role of 6-shogaol in this situation. It was shown that the level of sterol-regulatory element-binding protein-1 (SREBP-1), a critical transcription factor involved in lipid synthesis and metabolism, would be upregulated through Akt and p70S6K signaling pathways while CRC cells are cultured in ACM, which subsequently decreases the cell sensitivity to 5-FU cytotoxicity. Moreover, our results also demonstrated the antagonized role of 6-shogaol in attenuating the ACM effects on CRC cells through activating AMPK signaling. Overall, the present study elucidated the role of adipocyte-containing microenvironment in 5-FU resistance development of CRC through controlling the SREBP-1 level and further enhanced the concept of clinical application of 6-shogaol and AMPK signaling in CRC therapy.

Sign in / Sign up

Export Citation Format

Share Document