Abstract
Objectiveβ-Cell dysfunction plays a central role in the pathogenesis of type 2 diabetes (T2D), and the identification of novel approaches to improve β-cell function is essential to treat this disease. Baicalein, a flavonoid originally isolated from the root of Scutellaria Baicalensis, has been shown to have beneficial effects on β-cell function. Here, the authors investigated the molecular mechanism responsible for the protective effects of baicalein against palmitate (PA)-induced impaired β-cell function, and placed focus on the role of heme oxygenase (HO)-1.MethodsRat pancreatic β-cell line INS-1 cells or mouse pancreatic islets were cultured with PA (500 μM) to induce lipotoxicity in the presence or absence of baicalein (50 μM), and the expressions of the ER stress markers, ATF-3, CHOP and GRP78 were detected by Western blotting and/or qPCR. The involvement of HO-1 was evaluated by HO-1 siRNA transfection and using the HO-1 inhibitor ZnPP.ResultsBaicalein reduced PA-induced ER stress and inflammation and enhanced insulin secretion, and these effects were associated with the induction of HO-1. Furthermore, these protective effects were attenuated by ZnPP and by HO-1 siRNA. Pretreatment of PD98059 (an ERK inhibitor) significantly inhibited the protective effects of baicalein and blocked HO-1 induction. On the other hand, CO production by RuCO (a CO donor) ameliorated PA-induced ER stress, suggesting that CO production followed by HO-1 induction may contribute to the protective effects of baicalein against PA-induced β-cell dysfunction.ConclusionBaicalein protects pancreatic β-cells from PA-induced ER stress and inflammation via an ERK-HO-1 dependent pathway. The authors suggest HO-1 induction in pancreatic β-cells appears to be a promising therapeutic strategy for T2D.
Highlights
Pancreatic β-cell dysfunction plays a central role in the development of diabetes mellitus, and it has been documented that chronic exposure to elevated free fatty acid (FFA) levels causes β-cell dysfunction and apoptosis [1]
These protective effects were attenuated by zinc protoporphyrin IX (ZnPP) and by heme oxygenase (HO)-1 siRNA
CO production by RuCO ameliorated PA-induced endoplasmic reticulum (ER) stress, suggesting that CO production followed by Heme oxygenase-1 (HO-1) induction may contribute to the protective effects of baicalein against PA-induced β-cell dysfunction
Summary
Pancreatic β-cell dysfunction plays a central role in the development of diabetes mellitus, and it has been documented that chronic exposure to elevated free fatty acid (FFA) levels causes β-cell dysfunction and apoptosis [1]. The mechanism of lipotoxicity has not been fully clarified, accumulating evidence suggests the induction of endoplasmic reticulum (ER) stress might contribute to the detrimental effects of FFA on β-cells [2]. When ER homeostasis is disrupted by biochemical, physiological, or pathological stimuli, unfolded or misfolded proteins accumulate in ER lumen, overwhelm ER chaperons, such as, glucose-regulated protein 78 (GRP78), and cause ER stress. Moderate ER stress may represent a defense mechanism against external stimuli, but excessive or persistent ER stress eventually triggers programmed cell death or apoptosis by activating the caspase-12, C/EBP homology protein (CHOP), or the c-Jun-N-terminal kinase (JNK)-dependent pathway [3]. Considerable evidence has been presented that suggests ER stress contributes to FFAinduced β-cell dysfunction by upregulating pro-apoptotic effectors, such as, CHOP [4]. Pharmacological agents that alleviate ER stress may provide novel means of protecting β-cells from lipotoxicity
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