SCD1 is the critical signaling hub to mediate metabolic diseases: Mechanism and the development of its inhibitors

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 170, P. 115586 - 115586

Published: Dec. 1, 2023

Metabolic diseases, featured with dysregulated energy homeostasis, have become major global health challenges. Patients metabolic diseases high probability to manifest multiple complications in lipid metabolism, e.g. obesity, insulin resistance and fatty liver. Therefore, targeting the hub genes metabolism may systemically ameliorate along complications. Stearoyl-CoA desaturase 1(SCD1) is a key enzyme that desaturates saturated acids (SFAs) derived from de novo lipogenesis or diet generate monounsaturated (MUFAs). SCD1 maintains tissue homeostasis by responding to, integrating layers of endogenous stimuli, which mediated synthesized MUFAs. It critically regulates myriad physiological processes, including development, autophagy, tumorigenesis inflammation. Aberrant transcriptional epigenetic activation AMPK/ACC, SIRT1/PGC1α, NcDase/Wnt, etc, causes aberrant accumulation, thereby promoting progression non-alcoholic liver, diabetes cancer. This review assesses integrative mechanisms (patho)physiological functions inflammation autophagy. For translational perspective, potent inhibitors been developed treat various types We thus discuss multidisciplinary advances greatly accelerate development new inhibitors. In conclusion, besides cancer treatment, serve as promising target combat simultaneously.

Language: Английский

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Piezo1 regulates colon stem cells to maintain epithelial homeostasis through SCD1-Wnt-β-catenin and programming fatty acid metabolism

Cell Reports, Journal Year: 2025, Volume and Issue: 44(3), P. 115400 - 115400

Published: March 1, 2025

Highlights•Piezo1 inhibition promotes colon stem cell proliferation•SCD1 is downstream of Piezo1 to affect stemness•Impaired stemness associated with fatty acid metabolism in crypts•GsMTX4 has a protective effect on injured colitis colonoidsSummaryPiezo1, which maintains the integrity and function intestinal epithelial barrier, essential for colonic homeostasis. However, whether how regulates fate remains unclear. Here, we show that proliferation. Mechanistically, stearoyl-CoA 9-desaturase 1 (SCD1) by acting Wnt-β-catenin pathway. For mice, altered after knockdown activation was accompanied reprogrammed (FA) crypts. Notably, found GsMTX4 protects mouse human organoids. Our results elucidated role regulating normal postinjury fates through SCD1-Wnt-β-catenin SCD1-mediated FA desaturation process. These provide fresh perspectives mechanical factors therapeutic strategies related diseases.Graphical abstract

Language: Английский

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Gut Microbiota Remodeling and Intestinal Adaptation to Lipid Malabsorption After Enteroendocrine Cell Loss in Adult Mice

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2023, Volume and Issue: 15(6), P. 1443 - 1461

Published: Jan. 1, 2023

Background & AimsEnteroendocrine cells (EECs) and their hormones are essential regulators of whole-body energy homeostasis. EECs sense luminal nutrients microbial metabolites subsequently secrete various acting locally or at a distance. Impaired development during embryogenesis is life-threatening in newborn mice humans due to compromised nutrient absorption. However, the physiological importance EEC system adult has yet be directedly studied. Herein, we aimed determine long-term consequences total loss healthy adults on metabolism, intestinal transcriptome, microbiota.MethodsWe depleted by tamoxifen treatment Neurog3fl/fl; Villin-CreERT2 male mice. We studied cell differentiation, food efficiency, lipid absorption, microbiota composition, fecal metabolites, transcriptomic responses proximal distal small intestines lacking EECs. also determined high-fat diet-induced changes sorted Neurog3eYFP/+ EECs.ResultsInduction deficiency not unless fed with diet. Under standard chow diet, lose 10% weight impaired efficiency. Blood concentrations cholesterol, triglycerides, free fatty acids reduced, absorption delayed intestine. Genes controlling lipogenesis, carbohydrate neoglucogenesis upregulated. Microbiota composition rapidly altered after depletion characterized decreased α-diversity. Bacteroides Lactobacillus were progressively enriched, whereas Lachnospiraceae declined without impacting short-chain acid concentrations.ConclusionsEECs dispensable for survival under The absence impairs leading metabolic adaptations remodeling gut microbiota. Enteroendocrine Induction concentrations.

Language: Английский

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Stearoyl‐CoA Desaturase 1 Regulates Metabolism and Inflammation in Mouse Perivascular Adipose Tissue in Response to a High‐Fat Diet

Journal of Cellular Physiology, Journal Year: 2025, Volume and Issue: 240(2)

Published: Feb. 1, 2025

ABSTRACT The dysregulation of perivascular adipose tissue (PVAT) is a key contributor to obesity‐induced vascular dysfunction. Mouse periaortic divided into two parts: thoracic (TPVAT) and abdominal (APVAT). These parts have different physiological properties, which translate effects on the wall in onset metabolic syndrome. Stearoyl‐CoA desaturase 1 (SCD1) an enzyme that involved synthesis monounsaturated fatty acids has been shown play important role syndrome, including homeostasis. Despite considerable focus SCD1 development disorders, there currently lack knowledge relationship between PVAT. present study investigated deficiency lipolysis, β‐oxidation, mitochondrial dynamics, inflammation mouse TPVAT APVAT under high‐fat diet (HFD) feeding conditions. We found lower triglyceride levels PVAT −/− mice both vitro vivo compared with wildtype adipocytes, attributable activated lipolysis β‐oxidation. Moreover, HFD‐fed was characterized by higher oxidative phosphorylation complexes respiratory potential alterations morphology mice. Furthermore, showed signs greater pro‐inflammatory macrophage polarization inflammatory markers were induced HFD. This may be related accumulation free diacylglycerols, are enriched saturated acids. findings elucidate maintaining integrity.

Language: Английский

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Dietary oleic acid contributes to the regulation of food intake through the synthesis of intestinal oleoylethanolamide

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 17, 2023

Introduction Among the fatty acid ethanolamides (FAEs), oleoylethanolamide (OEA), linoleoylethanolamide (LEA), and palmitoylethanolamide (PEA) are reported to be involved in feeding regulation. In particular, OEA is well characterized as a satiety signal. Following food consumption, synthesized from oleic (OA) via an N -acyl phosphatidylethanolamine-specific phospholipase D-dependent pathway gastroenterocytes, induces by recruiting sensory fibers. Thus, we hypothesized that dietary OA important satiety-inducing molecule. However, there has been no direct demonstration of effect on induction without influence endogenous biosynthesis stearic (SA) or other FAEs. Methods this study, used two experimental diets test our hypothesis: (i) diet (OAD; 38.4 mg OA/g 7.2 SA/g) (ii) low (LOAD; 3.1 42.4 SA/g). Results Relative mice fed OAD, LOAD for weeks exhibited reduced levels jejunal but not LEA PEA. The LOAD-fed showed increase intake body weight gain. Moreover, LOAD-induced was immediately observed after switch whereas these effects were diminished back OAD. Furthermore, treatment with intake. Conclusion Collectively, results show key factor reduction mediated signaling.

Language: Английский

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It Takes Guts: Interactions of Intestinal Stearoyl CoA Desaturase 1 and Bile Acids

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2024, Volume and Issue: unknown, P. 101401 - 101401

Published: Sept. 1, 2024

Language: Английский

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SCD4 deficiency decreases cardiac steatosis and prevents cardiac remodeling in mice fed a high-fat diet

Journal of Lipid Research, Journal Year: 2024, Volume and Issue: 65(9), P. 100612 - 100612

Published: July 31, 2024

Stearoyl-CoA desaturase (SCD) is a lipogenic enzyme that catalyzes formation of the first double bond in carbon chain saturated fatty acids. Four isoforms SCD have been identified mice, most poorly characterized which SCD4, cardiac-specific. In present study, we investigated role SCD4 systemic and cardiac metabolism. We used wildtype (WT) global knockout mice were fed standard laboratory chow or high-fat diet (HFD). deficiency reduced body adiposity decreased hyperinsulinemia hypercholesterolemia HFD-fed mice. The loss preserved heart morphology HFD condition. Lipid accumulation myocardium SCD4-deficient HL-1 cardiomyocytes with knocked out Scd4 expression. This was associated an increase rate lipolysis and, more specifically, adipose triglyceride lipase (ATGL) activity. Possible mechanisms ATGL activation by include lower protein levels inhibitor G0S2 greater kinase A under lipid overload conditions. Moreover, observed higher intracellular Ca2+ cells silenced may explain response to levels. Additionally, inhibited mitochondrial enlargement, NADH overactivation, reactive oxygen species overproduction conclusion, activated lipolysis, resulting reduction steatosis, prevented induction left ventricular hypertrophy,

Language: Английский

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Retinoic acid regulates pyruvate dehydrogenase kinase 4 (Pdk4) to modulate fuel utilization in the adult heart: Insights from wild‐type and β‐carotene 9′,10′ oxygenase knockout mice

The FASEB Journal, Journal Year: 2022, Volume and Issue: 36(9)

Published: Aug. 25, 2022

Abstract Regulation of the pyruvate dehydrogenase (PDH) complex by kinase PDK4 enables heart to respond fluctuations in energy demands and substrate availability. Retinoic acid, transcriptionally active form vitamin A, is known be involved regulation cardiac function growth during embryogenesis as well under pathological conditions. Whether retinoic acid also maintains health physiological conditions unknown. However, A status intake its carotenoid precursor β‐carotene have been linked prevention diseases. Here, we provide vitro vivo evidence that regulates Pdk4 expression thus PDH activity. Furthermore, show mice lacking 9′,10′‐oxygenase (BCO2), only enzyme adult cleaves generate retinoids (vitamin derivatives), displayed insufficiency impaired metabolic flexibility a compromised PDK4/PDH pathway. These findings novel insights into functions regulating metabolism tissues, especially heart.

Language: Английский

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Spontaneous allelic variant in deafness–blindness gene Ush1g resulting in an expanded phenotype

Genes Brain & Behavior, Journal Year: 2023, Volume and Issue: 22(4)

Published: June 16, 2023

Abstract Relationships between novel phenotypic behaviors and specific genetic alterations are often discovered using target‐specific, directed mutagenesis or selection following chemical mutagenesis. An alternative approach is to exploit deficiencies in DNA repair pathways that maintain integrity response spontaneously induced damage. Mice deficient the glycosylase NEIL1 show elevated spontaneous mutations, which arise from translesion synthesis past oxidatively base Several litters of Neil1 knockout mice included animals were distinguished by their backwards‐walking behavior open‐field environments, while maintaining frantic forward movements home cage environment. Other manifestations swim test failures, head tilting circling. Mapping mutation conferred these showed introduction a stop codon at amino acid 4 Ush1g gene. bw/bw null displayed auditory vestibular defects commonly seen with mutations affecting inner‐ear hair‐cell function, including complete lack brainstem responses vestibular‐evoked potentials. As other Usher syndrome type I mutant mouse lines, hair cell phenotypes disorganized split bundles, as well altered distribution proteins for stereocilia localize tips row 1 2. Disruption bundle kinocilium displacement suggested USH1G essential forming cell's kinocilial links. Consistent models, had no substantial retinal degeneration compared bw /+ controls. In contrast previously described alleles, this new allele provides first model

Language: Английский

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Investigating the Effects of Dietary Bile Acids on Production Performance and Lipid Metabolism in Late-Phase Laying Hens

Animals, Journal Year: 2024, Volume and Issue: 14(24), P. 3554 - 3554

Published: Dec. 10, 2024

Multiply adverse effects including declines in production performance and excessive fat deposition were noticed with the extension of laying cycle hens, which are pertinent to animal welfare human food safety. This study aimed investigate effect dietary supplementation bile acids (BAs) on lipid metabolism late-phase hens. A total 144 70-week-old hens distributed into three treatments eight replicates per treatment, basal diet 0 (Ctrl), 95.01 (Low-BA), 189.99 mg/kg (High-BA) porcine BAs, respectively. The test period was from 70 75 weeks. BAs did not significantly alter during trial, whereas it increased (p < 0.05) follicles compared Ctrl diet. eggs fed BA exhibited > relative weight eggshell yolk color than those that consumed There no significant changes following treatment regarding serum profile. Dietary reduced triglyceride livers different extents, resulting decreased diameter area vacuoles liver tissues. low-dose mRNA levels fatty acid synthase (FASN) stearoyl-CoA desaturase (SCD), while promoting expression lipoprotein lipase (LPL) group (both p 0.05). Of note, expressions farnesoid X receptor (FXR), apical sodium-dependent transporter (ASBT), ileum acid-binding protein (IBABP) notably downregulated by treatment. had apparent performance, follicle frequency, weight, color. Moreover, a containing depressed ileal resorption hepatic reducing lipogenesis lipolysis, may have beneficial layers.

Language: Английский

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