Targeting PLIN2/PLIN5‐PPARγ: Sulforaphane Disturbs the Maturation of Lipid Droplets

Tian, Sicong; Lei, Peng; Teng, Chunying; Sun, Yao; Song, Xinyue; Li, Baolong; Shan, Yujuan

doi:10.1002/mnfr.201900183

Cited by 24 publications

(14 citation statements)

References 33 publications

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“…[ 57,58 ] Notably, some genes, such as Ubc and Plin2 , were involved in lipid oxidation and cell proliferation. [ 59,60 ] In addition, transcriptional alteration of some genes indicated that TDT could potentially induce immune responses in vivo. For example, CSF3 , a cytokine regulating the development and function of granulocytes and macrophages, was upregulated upon the drug treatment.…”

Section: Resultsmentioning

confidence: 99%

Near‐Infrared II Light‐Triggered Robust Carbon Radical Generation for Combined Photothermal and Thermodynamic Therapy of Hypoxic Tumors

Liu

Yang

Ling

et al. 2021

Adv Funct Materials

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Tumor hypoxia is a major cause of failure in cancer therapy, and there is almost no efficacious treatment for hypoxic tumors. Herein, an azo‐containing polymer (P2) is designed to encapsulate IR1061, and further covalently grafted with a tumor‐targeting tripeptide RGD to form P2@IR1061‐RGD NPs for combined photothermal and thermodynamic therapy (PTT/TDT) in the near‐infrared II (NIR II) biowindow (1000–1700 nm). Upon 1064 nm laser irradiation, IR1061 generates heat to break the azo bonds of P2, achieving robust carbon radical generation, which induces cancer cell death even under a hypoxic tumor microenvironment. RNA‐sequencing is first adopted to unveil the impact of combined PTT/TDT on the cell transcriptome and the corresponding pathways using 4T1 breast cancer cells. The dysregulated genes are involved in protein processing within the endoplasmic reticulum, cell cycle regulation, ubiquitin‐mediated proteolysis, and DNA replication pathways. The tumor inhibition rates on a 4T1 breast cancer model as well as on a patient‐derived xenograft model of hepatocellular carcinoma (PDXHCC) are 97% and 100%, and negligible systematic toxicity is observed. This study proposes the application of an azo‐containing polymer for safe and efficient combined PTT/TDT in the NIR II biowindow, as a promising strategy for clinical treatment of hypoxic tumors.

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Section: Resultsmentioning

confidence: 99%

Near‐Infrared II Light‐Triggered Robust Carbon Radical Generation for Combined Photothermal and Thermodynamic Therapy of Hypoxic Tumors

Liu

Yang

Ling

et al. 2021

Adv Funct Materials

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“…It is shown in our data that leptin treatment has increased the mRNA and protein expression of PPARγ, HSL, ATGL, and LPL. Other reports have found that PPARγ induces the accumulation of Plin5 [ 32 ], and further HSL and ATGL can interact with Plin5 to regulate lipolysis [ 22 , 33 ]. Interestingly, we found through preliminary experiments that the JAK2/STAT3 signaling pathway inhibitor (SD1008) and leptin co-treatment of 3T3-L1 did not cause changes in the expression of Plin5 mRNA, but the protein level of Plin5 was still significantly up-regulated.…”

Section: Discussionmentioning

confidence: 99%

Leptin Reduces Plin5 m6A Methylation through FTO to Regulate Lipolysis in Piglets

Wei

Sun

et al. 2021

IJMS

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Perilipin5 (Plin5) is a scaffold protein that plays an important role in lipid droplets (LD) formation, but the regulatory effect of leptin on it is unclear. Our study aimed to explore the underlying mechanisms by which leptin reduces the N6-methyladenosine (m6A) methylation of Plin5 through fat mass and obesity associated genes (FTO) and regulates the lipolysis. To this end, 24 Landrace male piglets (7.73 ± 0.38 kg) were randomly sorted into two groups, either a control group (Control, n = 12) or a 1 mg/kg leptin recombinant protein treatment group (Leptin, n = 12). After 4 weeks of treatment, the results showed that leptin treatment group had lower body weight, body fat percentage and blood lipid levels, but the levels of Plin5 mRNA and protein increased significantly in adipose tissue (p < 0.05). Leptin promotes the up-regulation of FTO expression level in vitro, which in turn leads to the decrease of Plin5 M6A methylation (p < 0.05). In in vitro porcine adipocytes, overexpression of FTO aggravated the decrease of M6A methylation and increased the expression of Plin5 protein, while the interference fragment of FTO reversed the decrease of m6A methylation (p < 0.05). Finally, the overexpression in vitro of Plin5 significantly reduces the size of LD, promotes the metabolism of triglycerides and the operation of the mitochondrial respiratory chain, and increases thermogenesis. This study clarified that leptin can regulate Plin5 M6A methylation by promoting FTO to affect the lipid metabolism and energy consumption, providing a theoretical basis for treating diseases related to obesity.

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“… 7 Recently it has been shown that perilipins are regulated by peroxisome proliferator-activated receptor gamma (PPAR-gamma) which, when inhibited results in the down-regulation of PLIN2 , affecting LSD formation. 59 RORA encodes nuclear receptor ROR-alpha, which is a regulator of lipid homeostasis through PPAR-gamma. 60 Hence, using TWAS, we have connected two genes involved in lipid metabolism through PPAR-gamma.…”

Section: Discussionmentioning

confidence: 99%

Defining functional variants associated with Alzheimer’s disease in the induced immune response

Harwood

Leonenko

Sims

et al. 2021

Brain Communications

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Defining the mechanisms involved in the aetiology of Alzheimer’s disease from genome-wide association studies alone is challenging since Alzheimer’s disease is polygenic and most genetic variants are non-coding. Non-coding Alzheimer’s disease risk variants can influence gene expression by affecting miRNA binding and those located within enhancers and within CTCF sites may influence gene expression through alterations in chromatin states. In addition, their function can be cell-type specific. They can function specifically in microglial enhancers thus affecting gene expression in the brain. Hence, transcriptome-wide association studies have been applied to test the genetic association between disease risk and cell/tissue-specific gene expression. Many Alzheimer’s disease—associated loci are involved in the pathways of the innate immune system. Both microglia, the primary immune cells of the brain, and monocytes which can infiltrate the brain and differentiate into activated macrophages, have roles in neuroinflammation and β-amyloid clearance through phagocytosis. In monocytes the function of regulatory variants can be context-specific after immune -stimulation. To dissect the variants associated with Alzheimer’s disease in the context of monocytes, we utilised data from naïve monocytes and following immune stimulation in vitro, in combination with genome-wide association studies of Alzheimer’s disease in transcriptome-wide association studies. Of the nine genes with statistically independent transcriptome-wide association signals, seven are located in known Alzheimer’s disease risk loci: BIN1, PTK2B, SPI1, MS4A4A, MS4A6E, APOE and PVR. The transcriptome-wide association signal for MS4A6E, PTK2B and PVR and the direction of effect replicated in an independent GWAS. Our analysis identified two novel candidate genes for Alzheimer’s disease risk, LACTB2 and PLIN2/ADRP. LACTB2 replicated in a transcriptome-wide association study using independent expression weights. LACTB2 and PLIN2/ADRP are involved in mitochondrial function and lipid metabolism respectively. Comparison of transcriptome-wide association study results from monocytes, whole blood and brain showed that the signal for PTK2B is specific to blood and MS4A6E is specific to LPS stimulated monocytes.

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Targeting PLIN2/PLIN5‐PPARγ: Sulforaphane Disturbs the Maturation of Lipid Droplets

Cited by 24 publications

References 33 publications

Near‐Infrared II Light‐Triggered Robust Carbon Radical Generation for Combined Photothermal and Thermodynamic Therapy of Hypoxic Tumors

Near‐Infrared II Light‐Triggered Robust Carbon Radical Generation for Combined Photothermal and Thermodynamic Therapy of Hypoxic Tumors

Leptin Reduces Plin5 m6A Methylation through FTO to Regulate Lipolysis in Piglets

Defining functional variants associated with Alzheimer’s disease in the induced immune response

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