Increased Unbound Retinol-binding Protein 4 Concentration Induces Apoptosis through Receptor-mediated Signaling

Chen, Chao-Hung; Hsieh, Tusty‐Jiuan; Lin, Kun‐Der; Lin, Hsing-Yi; Lee, Mei‐Yueh; Hung, Wei‐Wen; Hsiao, Pi‐Jung; Shin, Shyi–Jang

doi:10.1074/jbc.m111.301721

Cited by 31 publications

(26 citation statements)

References 37 publications

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“…6C). It is well known that the apoptotic death of renal cells is induced in CKD (36) and that renal apoptosis is induced by retinol (49). Accordingly, following incubation of the murine kidney carcinoma cell line, Renca, with either retinoic acid or retinol, caspase-3/7 activities, which are major indicators of apoptosis, increased significantly and dosedependently for both factors (Fig.…”

Section: Influence Of the Accumulation Of Serum Retinol On Renal Pathmentioning

confidence: 94%

Alterations of Hepatic Metabolism in Chronic Kidney Disease via D-box-binding Protein Aggravate the Renal Dysfunction

Hamamura

Matsumoto

Ikeda

et al. 2016

Journal of Biological Chemistry

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Chronic kidney disease (CKD) is associated with an increase in serum retinol; however, the underlying mechanisms of this disorder are poorly characterized. Here, we found that the alteration of hepatic metabolism induced the accumulation of serum retinol in 5/6 nephrectomy (5/6Nx) mice. The liver is the major organ responsible for retinol metabolism; accordingly, microarray analysis revealed that the hepatic expression of most CYP genes was changed in 5/6Nx mice. In addition, D-box-binding protein (DBP), which controls the expression of several CYP genes, was significantly decreased in these mice. Cyp3a11 and Cyp26a1, encoding key proteins in retinol metabolism, showed the greatest decrease in expression in 5/6Nx mice, a process mediated by the decreased expression of DBP. Furthermore, an increase of plasma transforming growth factor-␤1 (TGF-␤1) in 5/6Nx mice led to the decreased expression of the Dbp gene. Consistent with these findings, the alterations of retinol metabolism and renal dysfunction in 5/6Nx mice were ameliorated by administration of an anti-TGF-␤1 antibody. We also show that the accumulation of serum retinol induced renal apoptosis in 5/6Nx mice fed a normal diet, whereas renal dysfunction was reduced in mice fed a retinol-free diet. These findings indicate that constitutive Dbp expression plays an important role in mediating hepatic dysfunction under CKD. Thus, the aggravation of renal dysfunction in patients with CKD might be prevented by a recovery of hepatic function, potentially through therapies targeting DBP and retinol.

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Section: Influence Of the Accumulation Of Serum Retinol On Renal Pathmentioning

confidence: 94%

Alterations of Hepatic Metabolism in Chronic Kidney Disease via D-box-binding Protein Aggravate the Renal Dysfunction

Hamamura

Matsumoto

Ikeda

et al. 2016

Journal of Biological Chemistry

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“…One possibility is reduced STRA6-dependent action of RBP4, since some studies show that RBP4 may cause insulin resistance in a STRA6-dependent manner (16). Binding of RBP4 to STRA6 has been shown to stimulate JAK2/STAT5 signaling and upregulate STAT target genes, including that for SOCS3 in adipose tissue and muscle (15), and these effects of RBP4 are diminished in whole-body STRA6 null mice (18).…”

Section: Discussionmentioning

confidence: 99%

“…STRA6 is upregulated in some tumors, and its expression can be induced by retinoids and increased Wnt-1 expression in mammary epithelial cells (12). RBP4 mediates insulin resistance through STRA6-independent (13, 14) and STRA6-dependent pathways (15,16). Genetic data show that single nucleotide polymorphisms in STRA6 are associated with type 2 diabetes (17), raising the possibility that STRA6 plays an important role in altered metabolic states.…”

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confidence: 99%

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

Zemany

Kraus

Norseen

et al. 2014

Molecular and Cellular Biology

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bTo investigate the mechanisms by which elevated retinol-binding protein 4 (RBP4) causes insulin resistance, we studied the role of the high-affinity receptor for RBP4, STRA6 (stimulated by retinoic acid), in insulin resistance and obesity. In high-fat-diet-fed and ob/ob mice, STRA6 expression was decreased 70 to 95% in perigonadal adipocytes and both perigonadal and subcutaneous adipose stromovascular cells. To determine whether downregulation of STRA6 in adipocytes contributes to insulin resistance, we generated adipose-Stra6 ؊/؊ mice. Adipose-Stra6 ؊/؊ mice fed chow had decreased body weight, fat mass, leptin levels, insulin levels, and adipocyte number and increased expression of brown fat-selective markers in white adipose tissue. When fed a highfat diet, these mice had a mild improvement in insulin sensitivity at an age when adiposity was unchanged. STRA6 has been implicated in retinol uptake, but retinol uptake and the expression of retinoid homeostatic genes (encoding retinoic acid receptor ␤ [RAR␤], CYP26A1, and lecithin retinol acyltransferase) were not altered in adipocytes from adipose-Stra6 ؊/؊ mice, indicating that retinoid homeostasis was maintained with STRA6 knockdown. Thus, STRA6 reduction in adipocytes in adipose-Stra6 ؊/؊ mice fed chow resulted in leanness, which may contribute to their increased insulin sensitivity. However, in wild-type mice with high-fat-diet-induced obesity and in ob/ob mice, the marked downregulation of STRA6 in adipocytes and adipose stromovascular cells does not compensate for obesity-associated insulin resistance.T hree hundred fifty million people worldwide have diabetes (1), and the impact will be staggering if we do not develop more effective methods for early detection and treatment. Serum retinol-binding protein 4 (RBP4) is elevated in humans and rodents with insulin resistance and type 2 diabetes (2-4), and data suggest that it may play a causative role (4, 5). Injection of purified RBP4 or overexpression of RBP4 in mice causes insulin resistance (4). Furthermore, a gain-of-function polymorphism in the RBP4 promoter is associated with an 80% increased risk of developing diabetes in humans (5). In addition, epidemiologic studies in several ethnic backgrounds indicate that elevated RBP4 is an early marker of prediabetes (6) and metabolic syndrome (7,8) and is associated with a 3.6-fold increased risk of myocardial infarction (9).The mechanisms by which RBP4 causes insulin resistance and whether the actions of RBP4 depend on a receptor are questions of high interest in the field. STRA6 is a high-affinity cell surface receptor for RBP4 that mediates vitamin A uptake (10). STRA6 is highly expressed in blood-organ barriers and in the brain, eye, kidney, testis, and female reproductive tract, and it is absent from the liver (11). STRA6 is upregulated in some tumors, and its expression can be induced by retinoids and increased Wnt-1 expression in mammary epithelial cells (12). RBP4 mediates insulin resistance through STRA6-independent (13, 14) and STRA6-dependent pathwa...

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“…Since 2005, the literature has suggested linkages between serum RBP4 concentrations, obesity, impaired insulin responsiveness (103)(104)(105)(106)(107)132 ), fatty liver development (134)(135)(136)(137)(138)(139)(140), vessel wall disease ( 141,142 ), and heart disease ( 143 ). At the molecular level, the best studied of these effects is the action of excessive RBP4 acting as a cytokine activating a signaling cascade within cells, which can eventually lead to both direct and indirect alterations in insulin signaling.…”

Section: Retinoids In Adipose Tissuementioning

confidence: 99%

Retinol and retinyl esters: biochemistry and physiology

O’Byrne

Blaner

2013

Journal of Lipid Research

282

232

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The different retinoid forms present within the body (see Fig. 1 ) are generated by and large through modifi cations to the terminal polar end group of the molecule. Retinol and retinyl esters are the most abundant retinoid forms present in the body. All-trans -retinol is by defi nition vitamin A. When a fatty acyl group is esterifi ed to the hydroxyl terminus of retinol, a storage form of retinol, the retinyl ester, is formed. The most abundant retinyl esters present in the body are those of palmitic acid, oleic acid, stearic acid, and linoleic acid ( 6, 7 ). Although retinyl acetate can be found in supplements to foods and vitamin formulations, only long-chain acyl groups are esterifi ed to retinol by animals. Retinyl esters have no known biological activity aside from retinol storage and for serving as the substrate for the formation of the visual chromophore 11-cis -retinal, which must be formed from all-trans -retinyl ester through linked hydrolysis and isomerization reactions catalyzed by the enzyme RPE65 ( 3,4,8,9 ). Retinol is a transport form and a precursor form, which is enzymatically activated to retinoic acid via a two-step oxidation process. The primary role of retinal is in the eye where 11-cis -retinal is needed for visual pigment formation. In tissues, retinal serves as an intermediate in the synthesis of retinoic acid from retinol ( 6, 7 ). The literature also suggests a direct role for retinal in adipose tissue, where it was shown to inhibit adipogenesis and suppress peroxisome proliferator-activated receptor-␥ (PPAR ␥ ) and retinoid X receptor (RXR) responses in cell culture models and in mouse models fed high-fat diets ( 10 ).Abstract By defi nition, a vitamin is a substance that must be obtained regularly from the diet. Vitamin A must be acquired from the diet, but unlike most vitamins, it can also be stored within the body in relatively high levels. For humans living in developed nations or animals living in present-day vivariums, stored vitamin A concentrations can become relatively high, reaching levels that can protect against the adverse effects of insuffi cient vitamin A dietary intake for six months, or even much longer. The ability to accumulate vitamin A stores lessens the need for routinely consuming vitamin A in the diet, and this provides a selective advantage to the organism. The molecular processes that underlie this selective advantage include effi cient mechanisms to acquire vitamin A from the diet, effi cient and overlapping mechanisms for the transport of vitamin A in the circulation, a specifi c mechanism allowing for vitamin A storage, and a mechanism for mobilizing vitamin A from these stores in response to tissue needs. These processes are considered in this review. Since the identifi cation of fat-soluble A a century ago ( 1 ), retinoids (vitamin A and its natural and synthetic analogs) have been the most extensively studied of the fatsoluble vitamins. This research has identifi ed essential roles for retinoids in many different aspects of mammalian physiology, includ...

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Increased Unbound Retinol-binding Protein 4 Concentration Induces Apoptosis through Receptor-mediated Signaling

Cited by 31 publications

References 37 publications

Alterations of Hepatic Metabolism in Chronic Kidney Disease via D-box-binding Protein Aggravate the Renal Dysfunction

Alterations of Hepatic Metabolism in Chronic Kidney Disease via D-box-binding Protein Aggravate the Renal Dysfunction

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

Retinol and retinyl esters: biochemistry and physiology

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