Jiang, H.-M. | Search bioRxiv

bioRxiv2023

LDHA maintains the growth and migration of vascular smooth muscle cells and promotes neointima formation via crosstalk between K5 crotonylation and K76 mono-ubiquitination

Phenotypic plasticity of vascular smooth muscle cells (VSMCs) under stress is believed to be a key factor in neointima formation. Lactate dehydrogenase A (LDHA), a key enzyme for glycolysis, has been demonstrated to promote the proliferation and migration of VSMCs. However, the mechanism by which LDHA regulates this process is still unclear. Here we show that the crotonylation and mono-ubiquitination of LDHA are increased in platelet-derived growth factor (PDGF)-BB-induced proliferative VSMCs. Crotonylation at lysine 5 (K5) activates LDHA through tetramer formation to enhance lactate production and VSMCs growth. Mono-ubiquitination at K76 induces the translocation of LDHA into mitochondria, which promotes mitochondria fission and subsequent the formation of lamellipodia and podosomes, thereby enhancing VSMC migration and growth. Furthermore, the increase of crotonylation and ubiquitination were also observed in the carotid arteries of ligation injury mice. Deletion of LDHA K5 crotonylation or K76 mono-ubiquitination decreases ligation-induced neointima formation. Our study reveals a novel mechanism that combines VSMC metabolic reprogramming and behavioral abnormity through crosstalk between LDHA K5 crotonylation and K76 mono-ubiquitination.

biochemistry↗

bioRxiv2020

Temporal Metabolic Characteristics and Transcriptomic Landscape of Islets and Liver Reveal Dynamic Pathophysiology and Interorgan Crosstalk in High-fat Diet-induced Diabetes

ObjectiveHyperinsulinemia and insulin resistance are co-existing characteristics of type 2 diabetes, whereas the molecular mechanism underlying this deleterious cycle remains elusive. The temporal transcriptomic landscape of core organs responsible for insulin secretion (islets) and insulin action (liver) could provide new insights. MethodsThe longitudinal profiling of glucose metabolism, insulin sensitivity, islet architecture and secretion were conducted in C57BL/6N mice fed a high-fat diet (HFD) or chow diet for 24 weeks. RNA-sequencing of islets and liver were performed once every 4 weeks. Weighted gene co-expression network analysis and Ingenuity Pathway Analysis were applied to construct networks and evaluate co-ordinated molecular interactions between islets and liver. ResultsMice exhibited progressively deteriorated glucose homeostasis with hyperinsulinemia but impaired first-phase insulin secretion after 4 weeks on HFD. Insulin, glucagon and somatostatin secretion in response to glucose with or without palmitate gradually deteriorated from dysregulation to failure. Systemic insulin resistance developed over 24 weeks with variable time course in tissue-specific insulin action. Our transcriptomic datasets outlined the impact of HFD on dynamics of islet and liver molecular network at different stages. Correlation analyses revealed that both organs jointly programmed {beta}-cell compensatory adaption via cell proliferation at early phase and irreversible islet dysfunction by inappropriate immune response at later stage. Alternations of T cell subpopulations validated the participation of adaptive immune response through priming and amplification phases in diabetic progression. ConclusionOur data provide a comprehensive landscape of crosstalk between islets and liver in diet-induced diabetes, elucidating the development of islet dysfunction and insulin resistance. HighlightsO_LIDiet-induced diabetes is featured by transition from islet dysfunction to failure C_LIO_LIInsulin resistance develops with variable time course in different tissues C_LIO_LIDynamics of islet and liver molecular network interplay at different stages C_LIO_LICell proliferation and improper immune reaction mediated interorgan crosstalk C_LIO_LIAdaptive immune response participated via priming and amplification phases C_LI

cell biology↗