4‐Hydroxynonenal‐induced GPR109A (HCA2 receptor) activation elicits bipolar responses, Gαi‐mediated anti‐inflammatory effects and Gβγ‐mediated cell death

Gautam, Jaya; Banskota, Suhrid; Shah, S. P.; Jee, Jun-Goo; Kwon, Eunju; Wang, Ying; Kim, Dong Young; Chang, Hyun Wook; Kim, Jung-Ae

doi:10.1111/bph.14174

Cited by 27 publications

(14 citation statements)

References 66 publications

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“…Since the identification of GPR109A, a Gi/o‐coupled receptor, as the molecular target for niacin (20, 22, 36), most studies have focused on its pronounced hypolipidemic and cardioprotective action. Recent investigations have also shed light on the anti‐inflammatory and anti‐oxidative effects of GPR109A (22, 37–40). However, little attention has been paid to the potential of this receptor to favorably modulate de novo lipogenesis and energy homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Niacin fine‐tunes energy homeostasis through canonical GPR109A signaling

Cao

Lai

et al. 2018

FASEB j.

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The incidence of overweight and obesity has become a global public health problem, constituting a major risk factor for numerous comorbidities. Despite tremendous efforts, effective pharmacological agents for the treatment of obesity are still limited. Here, we showed that in contrast to lactate receptor GPR81, niacin receptor GPR109A‐deficient mice had progressive weight gain and hepatic fat accumulation. Using high‐fat diet–induced mouse model of obesity, we demonstrated that niacin treatment apparently protected against obesity without affecting food intake in wild‐type mice but not in GPR109A‐deficient mice. Further investigation showed that niacin treatment led to a remarkable inhibition of hepatic de novo lipogenesis. Additionally, we demonstrated that niacin treatment triggered brown adipose tissue and/or white adipose tissue thermogenic activity via activation of GPR109A. Moreover, we observed that mice exposed to niacin exhibited a dramatic decrease in intestinal absorption of sterols and fatty acids. Taken together, our findings demonstrate that acting on GPR109A, niacin shows the potential to maintain energy homeostasis through multipathways, representing a potential approach to the treatment of obesity, diabetes and cardiovascular disease.—Ye, L., Cao, Z., Lai, X., Wang, W., Guo, Z., Yan, L., Wang, Y., Shi, Y., Zhou, N. Niacin fine‐tunes energy homeostasis through canonical GPR109A signaling. FASEB J. 33, 4765–4779 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Niacin fine‐tunes energy homeostasis through canonical GPR109A signaling

Cao

Lai

et al. 2018

FASEB j.

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“…Since in response to hydroxynonenal GPR109A was demonstrated to induce excessive Ca 2+ mobilization and the subsequent cell death in the retinal pigmented and colon epithelial cells [47], we speculated that the same may occur in β-cells where GPR109A is expressed.…”

Section: Discussionmentioning

confidence: 97%

Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys

Boontem¹,

Yamashima²

2021

Preprint

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BackgroundFor their functions of insulin biosynthesis and glucose- and fatty acid- induced insulin secretion, the Langerhans β-cells require an intracellular milieu rich in oxygen. This requirement makes β-cells, with their constitutively low antioxidative defense, susceptible to the oxidative stress. Although much progress has been made in identifying its molecular basis in the experimental systems, whether the oxidative stress due to excessive fatty acids plays a crucial role in the Langerhans degeneration in primates is still debated.MethodsFocusing on Hsp70.1, which has dual functions as a molecular chaperone and lysosomal stabilizer, the mechanism of lipotoxicity to the Langerhans islet cells was studied using Japanese macaque monkeys (Macaca fuscata) after the consecutive injections of the lipid peroxidation product hydroxynonenal. Based on the ‘calpain-cathepsin hypothesis’ of ischemic neuronal death formulated in 1998, calpain activation, Hsp70.1 cleavage, and lysosomal integrity were studied by immunofluorescence histochemistry, electron microscopy and Western blotting.ResultsLight microscopy showed higher vacuole formation in the treated islet cells than in the control cells. Electron microscopy showed that vacuolar changes that were identified as enlarged rough endoplasmic reticula occurred mainly in β-cells followed by δ-cells. Intriguingly, both cell types showed a marked decrease in insulin and somatostatin granules. Furthermore, they exhibited marked increases in peroxisomes, autophagosomes/autolysosomes, lysosomal and peroxisomal membrane rupture/permeabilization, and mitochondrial degeneration. Disrupted peroxisomes were often localized in the close vicinity of degenerating mitochondria or autolysosomes. Immunofluorescence histochemical analysis showed an increased colocalization of activated μ-calpain and Hsp70.1 with the extralysosomal release of cathepsin B. Western blotting showed increases in μ-calpain activation, Hsp70.1 cleavage, and hydroxynonenal receptor GPR109A expression.ConclusionsTaken together, these data implicate hydroxynonenal in both the carbonylation of Hsp70.1 and the activation of μ-calpain. The calpain-mediated cleavage of the carbonyl group on Hsp70.1 after the hydroxynonenal-mediated carbonylation of Hsp70.1, may cause lysosomal membrane rupture/permeabilization. The low defense of primate Langerhans cells against exogenous hydroxynonenal and peroxisomally-generated hydrogen peroxide, was presumably overwhelmed to facilitate cell degeneration.

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“…These authors found that RPN supplementation may amplify the systemic inflammation-like condition in early lactation, and they suggested the markedly high-dosage RPN might be related to the indications of inflammation-like condition. To support this hypothesis, Gautam et al (77) found low concentration of niacin down-regulated the pro-inflammatory cytokines, but the high concentration of niacin induced cell apoptosis.…”

Section: Niacin Supplementation During Heat Stressmentioning

confidence: 98%

“…Recent studies demonstrated that nicotinic acid has a profound anti-inflammatory effect by an HCA 2 -dependent mechanism in mouse alveolar macrophages (75) , colonic macrophages, dendritic cells (76) , human retinal pigmented epithelial cells, kidney cells (77) , etc. This raises the question of whether nicotinic acid exerts a similar anti-inflammatory effect in ruminants.…”

Section: Niacin Supplementation During Heat Stressmentioning

confidence: 99%

Niacin nutrition and rumen-protected niacin supplementation in dairy cows: an updated review

2019

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As the precursor to NAD+ and NADP+, niacin is important for catabolic and anabolic redox reactions. In addition, niacin is known for its anti-lipolytic action via a hydroxycarboxylic acid-2-receptor-dependent mechanism. The anti-lipolytic effects of traditional free niacin supplementation during transition periods had been studied extensively, but the reported effects are ambiguous. In the past decade, a series of studies were conducted to evaluate the effects of rumen-protected niacin (RPN) on production performance and metabolic status in early lactation and on heat stress in dairy cows. Feeding RPN seems more effective than free niacin regarding increasing circulating niacin concentration. The rebound of plasma NEFA was found after termination of niacin abomasal infusion. Feeding RPN or infusion of niacin via the abomasum could suppress lipolysis and reduce insulin resistance in early lactation. Additionally, RPN supplementation could possibly relieve heat stress through vasodilation during moderate to severe heat stress condition. However, these beneficial effects of niacin supplementation have not always been observed. The inconsistent results across studies may be related to dosages of niacin supplementation, rebound of plasma NEFA concentration, stage of lactation or severity of heat stress. Overall, the current review is to present updated information on niacin nutrition in dairy cows and the recommendations are given for future research.

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4‐Hydroxynonenal‐induced GPR109A (HCA₂ receptor) activation elicits bipolar responses, G_αi‐mediated anti‐inflammatory effects and G_βγ‐mediated cell death

Cited by 27 publications

References 66 publications

Niacin fine‐tunes energy homeostasis through canonical GPR109A signaling

Niacin fine‐tunes energy homeostasis through canonical GPR109A signaling

Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys

Niacin nutrition and rumen-protected niacin supplementation in dairy cows: an updated review

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