Nicotinamide Riboside Ameliorates Hepatic Metaflammation by Modulating NLRP3 Inflammasome in a Rodent Model of Type 2 Diabetes

Lee, Hee Jae; Hong, Young-Shick; Jun, Woojin; Yang, Soo Jin

doi:10.1089/jmf.2015.3439

Cited by 56 publications

(49 citation statements)

References 41 publications

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“…NAFLD is characterized by metabolic derangement, insulin resistance, oxidative stress, and inflammation. KK/ HlJ mice fed a high fat diet showed hepatocyte injury and hepatic triglyceride accumulation, which are typical histopathological features of NAFLD (Ikejima et al 2007;Chen et al 2010;Lee et al 2015). Similar to the previous study, we also observed adipose infiltration and liver tissue structural damage in this study; however, RHL was able to improve the effects of this damage.…”

Section: Discussionsupporting

confidence: 90%

Rhein lysinate decreases inflammation and adipose infiltration in KK/HlJ diabetic mice with non-alcoholic fatty liver disease

et al. 2016

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The objective of this study was to investigate the protective effects of rhein lysinate (RHL) on the liver. Mice were divided into four groups: C57BL/J control, the KK/HlJ diabetic model, and 25 and 50 mg/kg/day RHL-treated KK/HlJ groups. The KK/HlJ diabetic mouse model was made by injecting STZ and feeding mice diabetic food. At 16 weeks, mice were sacrificed and their livers were harvested. The results indicated that compared with the C57BL/J control group, the body weights, liver weights and liver weight-to-body weight ratio were increased in KK/HlJ diabetic mice; however, these values were decreased following treatment with RHL. Compared with the C57BL/J control, KK/HlJ diabetic mice had a significantly lower level of SOD and GSH-px in their livers, but had a significantly higher level of MDA. However, these effects were ameliorated by RHL. Hepatic adipose infiltration was observed in KK/HlJ mice, but not in C57BL/J mice. RHL decreased the incidence of hepatic adipose infiltration and significantly decreased the expression of TNF-α, IL-6, NF-κB, SREBP-1c, and Fas, as well as the phosphorylation of NF-κB in the liver. In conclusion, RHL can improve hepatic function by decreasing hepatic adipose infiltration and the expression of inflammatory factors.

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Section: Discussionsupporting

confidence: 90%

Rhein lysinate decreases inflammation and adipose infiltration in KK/HlJ diabetic mice with non-alcoholic fatty liver disease

et al. 2016

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“…ROS promotes the dissociation of thioredoxin-interacting protein (TXNIP) from thioredoxin and allows TXNIP to bind to NLRP3, and subsequently stimulates NLRP3 activation in mouse beta cells [18]. It is now well recognized that the NLRP3 inflammasome is implicated in the pathophysiology of a number of diseases, including depression [19], type 2 diabetes [20], rheumatoid arthritis [21] and Alzheimer's disease [22]. Thus, the functional manipulation of the NLRP3 inflammasome has been thought to be a promising therapeutic strategy for these diseases [23], [24].…”

Section: Introductionmentioning

confidence: 99%

Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depression

et al. 2016

Redox Biology

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Mitochondrial uncoupling protein 2 (UCP2) has been well characterized to control the production of reactive oxygen species (ROS) and astrocytes are the major cells responsible for the ROS production and the inflammatory responses in the brain. However, the function of UCP2 in astrocytes and the contribution of astrocytic UCP2 to depression remain undefined. Herein, we demonstrated that UCP2 knockout (KO) mice displayed aggravated depressive-like behaviors, impaired neurogenesis, and enhanced loss of astrocytes in the chronic mild stress (CMS)-induced anhedonia model of depression. We further found that UCP2 ablation significantly enhanced the activation of the nod-like receptor protein 3 (NLRP3) inflammasome in the hippocampus and in astrocytes. Furthermore, UCP2 deficiency promoted the injury of mitochondria, the generation of ROS and the physical association between thioredoxin-interacting protein (TXNIP) and NLRP3 in astrocytes. Moreover, transiently expressing exogenous UCP2 partially rescued the deleterious effects of UCP2 ablation on the astrocytes. These data indicate that UCP2 negatively regulates the activation of NLRP3 inflammasome and inhibited the ROS-TXNIP-NLRP3 pathway in astrocytes. Collectively, our findings reveal that UCP2 regulates inflammation responses in astrocytes and plays an important role in the pathogenesis of depression and that UCP2 may be a promising therapeutic target for depression.

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“…The changes found in disease-free animals in our current and previous studies (Elamin et al, 2017) indicate that the use of ketone bodies as an energy source can be associated with a healthier metabolic phenotype and an enhanced redox state even in the absence of disease or senescence. Furthermore, the NAD + precursor nicotinamide ribose and PARP inhibitors are proposed to combat cancer and a host of inflammatory and neurodegenerative diseases (Basello and Scovassi, 2015; Lee et al, 2015; Ohmoto and Yachida, 2017; Vaur et al, 2017). We provide evidence that consuming a KD can mobilize similar mechanisms, and promote the metabolic resilience necessary to combat neurodegenerative and age-associated diseases.…”

Section: Discussionmentioning

confidence: 99%

Ketogenic Diet Modulates NAD+-Dependent Enzymes and Reduces DNA Damage in Hippocampus

Elamin

Ruskin

Masino

et al. 2018

Front. Cell. Neurosci.

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The ketogenic diet’s (KD) anti-seizure effects have long been documented. Recently, its therapeutic potential in multiple neurodegenerative and neurodevelopmental disorders has emerged. Yet experimental evidence for a fundamental mechanism underlying beneficial effects across numerous diseases remains lacking. We previously showed that feeding rats a KD produced an early (within 2 days) and persistent elevation of hippocampal nicotinamide adenine dinucleotide+ (NAD+), an essential metabolic coenzyme and signaling molecule. NAD+ is a marker of cellular health and a substrate for enzymes implicated in longevity and DNA damage repair such as sirtuins and poly-ADP ribose polymerase-1 (PARP-1). As a result, activation of NAD+-dependent enzymes’ downstream pathways could be the origin of KD’s broad beneficial effects. Here rats were fed ad libitum regular chow or KD for 2 days or 3 weeks and the levels of hippocampal sirtuins, PARP-1, and the oxidative DNA damage marker 8-hydroxy-2’-deoxyguanosine were quantified. We found a significant immediate and persistent increase in the collective activity of nuclear sirtuin enzymes, and a significant augmentation of Sirt1 mRNA at 2 days. Levels of PARP-1 and 8-hydroxy-2’-deoxyguanosine decreased after 2 days of treatment and further declined at 3 weeks. Our data show that a KD can rapidly modulate energy metabolism by acting on NAD+-dependent enzymes and their downstream pathways. Thus, therapy with a KD can potentially enhance brain health and increase overall healthspan via NAD+-related mechanisms that render cells more resilient against DNA damage and a host of metabolic, epileptic, neurodegenerative, or neurodevelopmental insults.

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Nicotinamide Riboside Ameliorates Hepatic Metaflammation by Modulating NLRP3 Inflammasome in a Rodent Model of Type 2 Diabetes

Cited by 56 publications

References 41 publications

Rhein lysinate decreases inflammation and adipose infiltration in KK/HlJ diabetic mice with non-alcoholic fatty liver disease

Rhein lysinate decreases inflammation and adipose infiltration in KK/HlJ diabetic mice with non-alcoholic fatty liver disease

Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depression

Ketogenic Diet Modulates NAD+-Dependent Enzymes and Reduces DNA Damage in Hippocampus

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