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

Sun, Qin; Xing, Xiaorui; Wang, Huanyu; Wan, Kang; Fan, Ruobing; Liu, Cheng; Wang, Yongjian; Wu, Wenyi; Wang, Yibing; Wang, Ru

doi:10.1016/j.biopha.2023.115586

Cited by 9 publications

(2 citation statements)

References 238 publications

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“…SCD1 serves as a metabolic hub connecting pathways related to lipid metabolism, autophagy, and inflammation. Elevated levels of SCD1 were associated with increased risk of MAFLD, diabetes and obesity 39 . Moreover, knockout of SCD1 in mice rendered them resistant to HFD-induced obesity 40 and prevented hepatic steatosis 41 , which was related to suppressed lipogenesis and enhanced fatty acid oxidation.…”

Section: Discussionmentioning

confidence: 98%

Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibitingde novolipogenesis and inflammationviamTOR/SREBP-1 and NF-κB signaling pathways

Stachowicz,

Czepiel,

Wiśniewska

et al. 2024

Preprint

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Background: Metabolic diseases that include obesity and metabolic-associated fatty liver disease (MAFLD) are a rapidly growing worldwide public health problem with unmet clinical need. The pathogenesis of MAFLD is very complex including abnormally increased lipogenesis, chronic inflammation, mitochondrial dysfunction, and oxidative stress. A growing body of evidence suggests that hydrogen sulfide (H2S) is an important player in the liver, impacting lipid metabolism and mitochondrial function. However, direct delivery of H2S to mitochondria has not been investigated as a therapeutic strategy in obesity-related metabolic disorders. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with a mitochondria sulfide delivery molecule (AP39) on the development of fatty liver and obesity in a high fat diet (HFD) fed mice. Results: Our results demonstrated that AP39 reduced fatty liver in HFD-fed mice, which was corresponded with decreased triglyceride content in the liver and plasma as well as increased GSH/GSSG ratio in the plasma. Furthermore, treatment with AP39 downregulated pathways related to biosynthesis of unsaturated fatty acids, lipoprotein assembly and PPAR signaling in the liver of HFD-fed mice. It also led to a decrease in de novo lipogenesis in the liver by downregulating mTOR/SREBP-1/SCD1 signaling pathway. Moreover, AP39 administration alleviated obesity in HFD-fed mice, which was reflected by reduced weight of mice and adipose tissue, decreased leptin levels in the plasma and upregulated expression of ATGL, a lipolysis enzyme in epididymal white adipose tissue (eWAT). Finally, AP39 reduced inflammation in the liver and eWAT measured as the expression of pro inflammatory markers (Il1b, Il6, Tnf, Mcp1), which was due to the downregulation of mTOR/NF-κB signaling pathway. Conclusions: Taken together, mitochondria-targeted sulfide delivery molecules could potentially provide a novel therapeutic approach to the treatment/prevention of obesity-related metabolic disorders.

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Section: Discussionmentioning

confidence: 98%

Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibitingde novolipogenesis and inflammationviamTOR/SREBP-1 and NF-κB signaling pathways

Stachowicz,

Czepiel,

Wiśniewska

et al. 2024

Preprint

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“…Also, the increased concentration of leptin could repress the Scd-1 expression [ 64 ]. As Sun et al recently reviewed, Scd-1 is a pivotal metabolic homeostasis regulator, often displaying dual roles in adiposity and insulin resistance [ 65 ]. Previous observations regarding the role of Cish in metabolism have been controversial.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Ovariectomy and Estradiol Substitution on the Metabolic Parameters and Transcriptomic Profile of Adipose Tissue in a Prediabetic Model

Marková,

Hüttl,

Miklánková

et al. 2024

Antioxidants

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Menopause brings about profound physiological changes, including the acceleration of insulin resistance and other abnormalities, in which adipose tissue can play a significant role. This study analyzed the effect of ovariectomy and estradiol substitution on the metabolic parameters and transcriptomic profile of adipose tissue in prediabetic females of hereditary hypertriglyceridemic rats (HHTgs). The HHTgs underwent ovariectomy (OVX) or sham surgery (SHAM), and half of the OVX group received 17β-estradiol (OVX+E2) post-surgery. Ovariectomy resulted in weight gain, an impaired glucose tolerance, ectopic triglyceride (TG) deposition, and insulin resistance exemplified by impaired glycogenesis and lipogenesis. Estradiol alleviated some of the disorders associated with ovariectomy; in particular, it improved insulin sensitivity and reduced TG deposition. A transcriptomic analysis of perimetrial adipose tissue revealed 809 differentially expressed transcripts in the OVX vs. SHAM groups, mostly pertaining to the regulation of lipid and glucose metabolism, and oxidative stress. Estradiol substitution affected 1049 transcripts with overrepresentation in the signaling pathways of lipid metabolism. The principal component and hierarchical clustering analyses of transcriptome shifts corroborated the metabolic data, showing a closer resemblance between the OVX+E2 and SHAM groups compared to the OVX group. Changes in the adipose tissue transcriptome may contribute to metabolic abnormalities accompanying ovariectomy-induced menopause in HHTg females. Estradiol substitution may partially mitigate some of these disorders.

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Tartaric acid ameliorates experimental non-alcoholic fatty liver disease by activating the AMP-activated protein kinase signaling pathway

Pei,

He,

Wang

et al. 2024

European Journal of Pharmacology

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

Cited by 9 publications

References 238 publications

Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibitingde novolipogenesis and inflammationviamTOR/SREBP-1 and NF-κB signaling pathways

Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibitingde novolipogenesis and inflammationviamTOR/SREBP-1 and NF-κB signaling pathways

The Effect of Ovariectomy and Estradiol Substitution on the Metabolic Parameters and Transcriptomic Profile of Adipose Tissue in a Prediabetic Model

Tartaric acid ameliorates experimental non-alcoholic fatty liver disease by activating the AMP-activated protein kinase signaling pathway

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