Vitamin A deficiency causes islet dysfunction by inducing islet stellate cell activation via cellular retinol binding protein 1

Abstract

Background: Vitamin A (VA) plays an essential role in pancreatic homeostasis. Islet stellate cells (ISCs) are VA-storing cells in pancreatic islets. Herein, we have investigated the effect of VA on glucose homeostasis trough regulation of ISCs function in dietary VA deficiency model mice. Methods: Male C57BL/6 mice were randomly fed a VA-sufficient, a VA-deficient (VAD) or a VAD-rescued diet. Glucose metabolism was assessed by glucose tolerance tests and immunohistochemistry. ISCs activation degree was evaluated by immunofluorescence, quantitative PCR and western blotting in both, retinol-treated cultured ISCs and model mice. Changes in ISCs phenotype and their effect on islets were assessed by lentiviral transduction and enzyme-linked immunosorbent assays in a co-culture system. Results: VAD mice showed irregular shaped islet, glucose intolerance, islet size distribution excursions, and upregulated expression of α-smooth muscle actin (α-SMA, marker of ISCs activation). Reintroduction of dietary VA restored pancreatic VA levels, endocrine hormone profiles, and inhibited ISCs activation. Incubation with retinol increased the expression of VA signaling factors in ISCs, including cellular retinol binding protein 1 (CRBP1). The knockdown of CRBP1 maintained the quiescent ISCs phenotype and reduced the damage of activated ISCs on islet function. Conclusions: VA deficiency reduced islet function by activating ISCs in VAD mice. Restoring ISCs quiescence via CRBP1 inhibition could reverse the impairment of islet function caused by activated ISCs exposure.

Cardiometabolic Risk Factors leading to Diabetes Mellitus among the Young (YOD) from the 8th Philippine National Nutrition Survey

“…Reduced β cell mass increased α cell mass, with hyperglycemia and altered serum insulin and glucagon profiles. 39 Furthermore, micronutrient deficiency may also be related to developing macro and microvascular complications of diabetes, as diabetic patients with vitamin A deficiency are also seen to develop nonhealing foot ulcers. 40 The continued high prevalence of diabetes in both young and older age groups in the Philippines suggests a complex interplay of many different factors leading to its development.…”

Screening and Identification of Key Genes for Activation of Islet Stellate Cell

“…In T2DM, ISCs transform from a quiescent into an activated state. ISCs express a large amount of α-SMA and exhibit increased proliferation and migration rates, as well as the enhanced synthesis and deposition of ECM components during activation, which are associated with fibrogenic response ( 21 , 29 ). Therefore, it is necessary to understand the mechanisms leading to the activation of ISCs in order to identify potential targets to prevent the progression of islet fibrosis in T2DM.…”

Vitamin A and Its Multi-Effects on Pancreas: Recent Advances and Prospects

“…Mice lacking the RA-synthesizing enzyme aldehyde dehydrogenase-1 (ALDH-1) showed lower expression levels of the key gluconeogenic enzymes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, the latter of which is an RA-inducible target gene containing a specific RA-receptor binding site as an RA response element ( 61 ). Other findings indicated an additional mechanism through which VA affects islet function by governing islets size distribution was correlated with the α-SMA-positive ISC pool in a mouse model of dietary VAD ( 29 ).…”

“…Zhou et al. ( 29 ) found that prolonged VA deficiency (VAD) alters the phenotype of resting islet stellate cells (ISCs, the subset of PSCs) compared with that of myofibroblast-like cells with increased α-SMA expression. Moreover, reintroduction of dietary VA to VA-deficient mice restores endocrine hormone profiles and induced ISCs/PSCs to become “re-quiescent,” similar to the results observed following induction of the VA-sufficient (VAS)-controlled ISCs/PSCs phenotype.…”

“…Thus, ATRA treatment affected the ability of PSCs to sense extracellular mechanical cues and induces cytoskeletal changes consistent with a resting-like phenotype. Zhou et al ( 29 ) found CRBP1 knockdown restored the polygonal appearance of quiescent ISCs, and reduced the expression of activation-related proteins, such as α-SMA and collagen synthesis, thereby producing a resting-state phenotype. Maintaining ISCs being quiescent state enhanced glucose-induced insulin release and basal insulin secretion.…”