Haixia Ding1, Fujun Wang2, Xuelian Shi3, Hongfang Ma1, Yaping Du1, Lin Hou1, Na Xing1. 1. Department of Endocrinology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, China. 2. Department of Endocrinology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, China. Electronic address: wangfujun139@126.com. 3. Department of Pain rehabilitation, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Abstract
BACKGROUND: Type 1 diabetes (T1DM) severely threatens human health, and the dysfunction of insulin-secreting β cells in islets is related to the reduced PDX-1 expression. It has been reported that long non-coding RNA MALAT1 regulates β cell function, while the potential mechanism is unclear. METHODS: Islets were isolated from non-obese diabetic (NOD) mice and wild type (WT) mice. Mouse islets and β cell line (Min6) were stimulated by IL-1β. The expression of MALAT1 was determined using real-time PCR, while the PDX-1 protein expression was determined using western blotting. ChIP-qPCR was carried out to determine the histone acetylation of the PDX-1 promoter. RESULTS: In NOD islets and IL-1β-stimulated Min6 cells, the expression of MALAT1 was increased, while the mRNA and protein levels of PDX-1 were decreased at an age/time-dependent manner. Overexpressing MALAT1 suppressed the H3 histone acetylation of the PDX-1 promoter, inhibiting both mRNA and protein expressions of PDX-1. Knocking down MALAT1 restored the decrease of the histone acetylation of the PDX-1 promoter, as well as the PDX-1 expression, which was reduced by IL-1β stimulation. Under high glucose stimulation, the overexpression of PDX-1 alone restored the insulin secretion which was inhibited by the simultaneous overexpression of MALAT1 and PDX-1. Under high glucose and IL-1β stimulation, the simultaneous knockdown of MALAT1 and PDX-1 reduced the enhancement of the insulin secretion which was raised by knocking down MALAT1 alone. CONCLUSION: MALAT1 induces the dysfunction of β cells via reducing the H3 histone acetylation of the PDX-1 promoter and subsequently inhibiting the expression of PDX-1, thus suppressing the insulin secretion.
BACKGROUND: Type 1 diabetes (T1DM) severely threatens human health, and the dysfunction of insulin-secreting β cells in islets is related to the reduced PDX-1 expression. It has been reported that long non-coding RNA MALAT1 regulates β cell function, while the potential mechanism is unclear. METHODS: Islets were isolated from non-obese diabetic (NOD) mice and wild type (WT) mice. Mouse islets and β cell line (Min6) were stimulated by IL-1β. The expression of MALAT1 was determined using real-time PCR, while the PDX-1 protein expression was determined using western blotting. ChIP-qPCR was carried out to determine the histone acetylation of the PDX-1 promoter. RESULTS: In NOD islets and IL-1β-stimulated Min6 cells, the expression of MALAT1 was increased, while the mRNA and protein levels of PDX-1 were decreased at an age/time-dependent manner. Overexpressing MALAT1 suppressed the H3 histone acetylation of the PDX-1 promoter, inhibiting both mRNA and protein expressions of PDX-1. Knocking down MALAT1 restored the decrease of the histone acetylation of the PDX-1 promoter, as well as the PDX-1 expression, which was reduced by IL-1β stimulation. Under high glucose stimulation, the overexpression of PDX-1 alone restored the insulin secretion which was inhibited by the simultaneous overexpression of MALAT1 and PDX-1. Under high glucose and IL-1β stimulation, the simultaneous knockdown of MALAT1 and PDX-1 reduced the enhancement of the insulin secretion which was raised by knocking down MALAT1 alone. CONCLUSION:MALAT1 induces the dysfunction of β cells via reducing the H3 histone acetylation of the PDX-1 promoter and subsequently inhibiting the expression of PDX-1, thus suppressing the insulin secretion.
Authors: Aritania Sousa Santos; Edécio Cunha-Neto; Nelson Vinicius Gonfinetti; Fernanda Bernardi Bertonha; Pauline Brochet; Aurelie Bergon; Carlos Alberto Moreira-Filho; Christophe Chevillard; Maria Elizabeth Rossi da Silva Journal: Front Immunol Date: 2022-01-04 Impact factor: 7.561