Dataset Information

PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle.

ABSTRACT:

Introduction

Endoplasmic reticulum (ER) stress has emerged as a key player in insulin resistance (IR) progression in skeletal muscle. Recent reports revealed that ER stress-induced the expression of protein disulfide isomerase family a member 4 (PDIA4), which may be involved in IR-related diseases. A previous study showed that metformin modulated ER stress-induced IR. However, it remained unclear whether metformin alleviated IR by regulating PDIA4 expression in skeletal muscle.

Methods

Herein, we used palmitate-induced IR in C2C12 cells and a high-fat diet-induced IR mouse model to document the relations between metformin, IR, and PDIA4.

Results

In C2C12 cells, palmitate-induced IR increased inflammatory cytokines and PDIA4 expression. Besides, knocking down PDIA4 decreased palmitate-induced IR and inflammation in C2C12 cells. Furthermore, metformin modulated PDIA4 expression and alleviated IR both in vitro and in vivo. In addition, serum PDIA4 concentrations are associated with IR and inflammatory cytokines levels in human subjects.

Discussion

Thus, this study is the first to demonstrate that PDIA4 participates in the metformin-induced effects on skeletal muscle IR and indicates that PDIA4 is a potential novel therapeutic target for directly alleviating IR.

SUBMITTER: Lee CH

PROVIDER: S-EPMC9816868 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle.

Lee Chien-Hsing CH Chiang Chi-Fu CF Lin Fu-Huang FH Kuo Feng-Chih FC Su Sheng-Chiang SC Huang Chia-Luen CL Li Peng-Fei PF Liu Jhih-Syuan JS Lu Chieh-Hua CH Hsieh Chang-Hsun CH Hung Yi-Jen YJ Shieh Yi-Shing YS

Frontiers in endocrinology 20221223

<h4>Introduction</h4>Endoplasmic reticulum (ER) stress has emerged as a key player in insulin resistance (IR) progression in skeletal muscle. Recent reports revealed that ER stress-induced the expression of protein disulfide isomerase family a member 4 (PDIA4), which may be involved in IR-related diseases. A previous study showed that metformin modulated ER stress-induced IR. However, it remained unclear whether metformin alleviated IR by regulating PDIA4 expression in skeletal muscle.<h4>Method ...[more]

PMID: 36619574

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Project description:AimsChronic alcohol abuse causes steatohepatitis with insulin resistance, which impairs hepatocellular growth, survival and metabolism. However, growing evidence supports the concept that progressive alcohol-related liver injury may be mediated by concurrent mal-signaling through other networks that promote insulin resistance, e.g. pro-inflammatory, pro-ceramide and endoplasmic reticulum (ER) stress cascades.MethodsUsing the Long Evans rat model of chronic ethanol feeding, we characterized the histopathologic and ultrastructural features of steatohepatitis in relation to biochemical and molecular indices of tissue injury, inflammation, insulin resistance, dysregulated lipid metabolism and ER stress.ResultsChronic steatohepatitis with early chicken-wire fibrosis was associated with enlargement of mitochondria and disruption of ER structure by electron microscopy, elevated indices of lipid storage, lipid peroxidation and DNA damage, increased activation of pro-inflammatory cytokines, impaired signaling through the insulin receptor (InR), InR substrate-1, Akt, ribosomal protein S6 kinase and proline-rich Akt substrate 40 kDa, glycogen synthase kinase 3β activation and constitutive up-regulation of ceramide and ER stress-related genes. Liquid chromatography coupled with tandem mass spectrometry demonstrated altered ceramide profiles with higher levels of C14 and C18, and reduced C16 species in ethanol-exposed livers.ConclusionThe histopathologic and ultrastructural abnormalities in chronic alcohol-related steatohepatitis are associated with persistent hepatic insulin resistance and pro-inflammatory cytokine activation, dysregulated lipid metabolism with altered ceramide profiles and both ER and oxidative stress. Corresponding increases in lipid peroxidation, DNA damage and protein carbonylation may have contributed to the chronicity and progression of disease. The findings herein suggest that multi-pronged therapeutic strategies may be needed for effective treatment of chronic alcoholic liver disease in humans.

Dataset Information

PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle.

Introduction

Methods

Results

Discussion

Publications

PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle.

Similar Datasets

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