SREBP1c-PAX4 Axis Mediates Pancreatic β-Cell Compensatory Responses Upon Metabolic Stress

Lee, Gung; Jang, Hyejeong; Kim, Ye Young; Choe, Sung Sik; Kong, Jinuk; Hwang, Injae; Park, Jeu; Im, Seung‐Soon; Kim, Jae Bum

doi:10.2337/db18-0556

Cited by 18 publications

(15 citation statements)

References 47 publications

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“…In contrast, after exposure to PA, a large number of lipid droplets were accumulated in the cytoplasm. SREBP1c, a transcription factor responsible for fatty acid synthesis (17), was increased in PAstimulated INS-1 cells (Figure 3B). The real-time PCR array revealed a profound upregulation of genes implicated in fatty acid synthesis (i.e., Fas, SCD1), uptake (i.e., Cd36, Fabp4), hydrolysis (i.e., Lpl), and storage (i.e., Plin5) after PA stimulation compared to the control group (Figure 3C).…”

Section: Pa Induced Lipid Accumulation In Ins-1 Cellsmentioning

confidence: 97%

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JunD Regulates Pancreatic β-Cells Function by Altering Lipid Accumulation

et al. 2021

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The impairment of pancreatic β-cells function is partly caused by lipotoxicity, which aggravates the development of type 2 diabetes mellitus. Activator Protein 1 member JunD modulates apoptosis and oxidative stress. Recently, it has been found that JunD regulates lipid metabolism in hepatocytes and cardiomyocytes. Here, we studied the role of JunD in pancreatic β-cells. The lipotoxic effects of palmitic acid on INS-1 cells were measured, and JunD small-interfering RNA was used to assess the effect of JunD in regulating lipid metabolism and insulin secretion. The results showed that palmitic acid stimulation induced the overexpression of JunD, impaired glucose-stimulated insulin secretion, and increased intracellular lipid accumulation of β-cells. Moreover, the gene expression involved in lipid metabolism (Scd1, Fabp4, Fas, Cd36, Lpl, and Plin5) was upregulated, while gene expression involved in the pancreatic β-cells function (such as Pdx1, Nkx6.1, Glut2, and Irs-2) was decreased. Gene silencing of JunD reversed the lipotoxic effects induced by PA on β-cells. These results suggested that JunD regulated the function of pancreatic β-cells by altering lipid accumulation.

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Section: Pa Induced Lipid Accumulation In Ins-1 Cellsmentioning

confidence: 97%

“…Then we evaluated whether JunD was activated in PAinduced INS-1 cells. PA is widely used to induce lipotoxicity mimicking the environment of T2DM (17). The CCK8 assay was performed to determine the concentration and stimulation time of PA (Figure S1A).…”

Section: Jund Was Activated In Islets Of T2dm Mice and Pa-stimulated Ins-1 Cellsmentioning

confidence: 99%

JunD Regulates Pancreatic β-Cells Function by Altering Lipid Accumulation

et al. 2021

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“…Chromatin Immunoprecipitation-Quantitative Real-time PCR Chromatin immunoprecipitation (ChIP) was performed as described previously (16). Primary adipocytes were isolated from epididymal white adipose tissue (eWAT), subjected to crosslinking with 1% formaldehyde for 10 min, and lysed with lysis buffer (1% SDS, 10 mmol/L EDTA, 50 mmol/L Tris-HCl [pH 8.1], and protease inhibitor cocktail).…”

Section: Yeast Two-hybrid Screeningmentioning

confidence: 99%

RNF20 Functions as a Transcriptional Coactivator for PPARγ by Promoting NCoR1 Degradation in Adipocytes

Jeon

Lee

et al. 2019

Diabetes

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Adipose tissue is the key organ coordinating wholebody energy homeostasis. Although it has been reported that ring finger protein 20 (RNF20) regulates lipid metabolism in the liver and kidney, the roles of RNF20 in adipose tissue have not been explored. Here, we demonstrate that RNF20 promotes adipogenesis by potentiating the transcriptional activity of peroxisome proliferator-activated receptor-g (PPARg). Under normal chow diet feeding, Rnf20 defective (Rnf20 1/2) mice exhibited reduced fat mass with smaller adipocytes compared with wild-type littermates. In addition, highfat diet-fed Rnf20 1/2 mice alleviated systemic insulin resistance accompanied by a reduced expansion of fat tissue. Quantitative proteomic analyses revealed significantly decreased levels of PPARg target proteins in adipose tissue of Rnf20 1/2 mice. Mechanistically, RNF20 promoted proteasomal degradation of nuclear corepressor 1 (NCoR1), which led to stimulation of the transcriptional activity of PPARg. Collectively, these data suggest that RNF20-NCoR1 is a novel axis in adipocyte biology through fine-tuning the transcriptional activity of PPARg.

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“…The F-actin and G-actin ratios were determined by densitometry by using ImageJ ( Quantitative RT-PCR. Quantitative reverse transcription-PCR (qRT-PCR) was performed as previously described (52). Briefly, total RNA was extracted from 3T3-L1 adipocytes and primary adipocytes were isolated from eWAT, iWAT, and BAT.…”

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confidence: 99%

During Adipocyte Remodeling, Lipid Droplet Configurations Regulate Insulin Sensitivity through F-Actin and G-Actin Reorganization

Kim

Park

et al. 2019

Molecular and Cellular Biology

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Adipocytes have unique morphological traits in insulin sensitivity control. However, how the appearance of adipocytes can determine insulin sensitivity has not been understood. Here, we demonstrate that actin cytoskeleton reorganization upon lipid droplet (LD) configurations in adipocytes plays important roles in insulin-dependent glucose uptake by regulating GLUT4 trafficking. Compared to white adipocytes, brown/beige adipocytes with multilocular LDs exhibited well-developed filamentous actin (F-actin) structure and potentiated GLUT4 translocation to the plasma membrane in the presence of insulin. In contrast, LD enlargement and unilocularization in adipocytes downregulated cortical F-actin formation, eventually leading to decreased F-actin-to-globular actin (G-actin) ratio and suppression of insulin-dependent GLUT4 trafficking. Pharmacological inhibition of actin polymerization accompanied with impaired F/G-actin dynamics reduced glucose uptake in adipose tissue and conferred systemic insulin resistance in mice. Thus, our study reveals that adipocyte remodeling with different LD configurations could be an important factor to determine insulin sensitivity by modulating F/G-actin dynamics.

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SREBP1c-PAX4 Axis Mediates Pancreatic β-Cell Compensatory Responses Upon Metabolic Stress

Cited by 18 publications

References 47 publications

JunD Regulates Pancreatic β-Cells Function by Altering Lipid Accumulation

JunD Regulates Pancreatic β-Cells Function by Altering Lipid Accumulation

RNF20 Functions as a Transcriptional Coactivator for PPARγ by Promoting NCoR1 Degradation in Adipocytes

During Adipocyte Remodeling, Lipid Droplet Configurations Regulate Insulin Sensitivity through F-Actin and G-Actin Reorganization

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