Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice

Gariani, Karim; Menzies, Keir J.; Ryu, Dongryeol; Wegner, Casey; Wang, Xu; Ropelle, Eduardo Rochete; Moullan, Norman; Zhang, Hongbo; Perino, Alessia; Lemos, Vera; Kim, Bohkyung; Park, Young‐Ki; Piersigilli, Alessandra; Pham, Tho X.; Yang, Yue; Ku, Chai Siah; Koo, Sung I.; Fomitchova, Anna; Cantó, Carlos; Schoonjans, Kristina; Sauve, Anthony A.; Lee, Ji‐Young; Auwerx, Johan

doi:10.1002/hep.28245

Cited by 299 publications

(328 citation statements)

References 44 publications

Supporting

Mentioning

303

Contrasting

Unclassified

Order By: Relevance

“…NAD + declines with age (47,51), and supplementation with NAD + precursors can delay aging, liver disease, and vascular dysfunction (52)(53)(54). NAD + precursors, such as nicotinamide riboside, can be used safely in humans (55,56).…”

Section: Discussionmentioning

confidence: 99%

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Yanagida

Knight

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

View full text Add to dashboard Cite

The retinal pigment epithelium (RPE) is a monolayer of pigmented cells that requires an active metabolism to maintain outer retinal homeostasis and compensate for oxidative stress. Using 13 C metabolic flux analysis in human RPE cells, we found that RPE has an exceptionally high capacity for reductive carboxylation, a metabolic pathway that has recently garnered significant interest because of its role in cancer cell survival. The capacity for reductive carboxylation in RPE exceeds that of all other cells tested, including retina, neural tissue, glial cells, and a cancer cell line. Loss of reductive carboxylation disrupts redox balance and increases RPE sensitivity to oxidative damage, suggesting that deficiencies of reductive carboxylation may contribute to RPE cell death. Supporting reductive carboxylation by supplementation with an NAD + precursor or its substrate α-ketoglutarate or treatment with a poly(ADP ribose) polymerase inhibitor protects reductive carboxylation and RPE viability from excessive oxidative stress. The ability of these treatments to rescue RPE could be the basis for an effective strategy to treat blinding diseases caused by RPE dysfunction.reductive carboxylation | RPE | metabolism | age-related macular degeneration | oxidative stress T he retinal pigment epithelium (RPE) is a monolayer of postmitotic cells situated between the photoreceptors of the retina and the choroidal blood supply. The interaction of the RPE and photoreceptors is critical to maintaining vision. Functions of the RPE include phagocytosis of shed photoreceptor outer segments, recycling of retinoids, production and secretion of cytokines and chemokines, and mediating the exchange of nutrients and metabolites between the choroid and photoreceptors (1, 2). RPE cells provide crucial metabolic support for the retina.RPE dysfunction can lead to photoreceptor death and retinal degenerative disease, such as age-related macular degeneration (AMD), which is the leading cause of irreversible vision loss in the elderly human population (3-5). RPE cells are exposed to ongoing oxidative stress from the combined effects of light, choroidal O 2 , polyunsaturated fatty acids, and retinoids (6). The resulting impairment in RPE energy metabolism and function by oxidative stress is one likely mechanism for the pathogenesis of AMD (3, 7-11).Mitochondria support the active energy metabolism of the RPE (10-12). A recent report showed that RPE is less stable and less able to support the retina when it is forced to rely on glycolytic rather than mitochondrial metabolism (13). Another recent report supports the importance of mitochondria in RPE by showing that bolstering mitochondrial activity makes these cells more resilient to oxidative damage (14).In mitochondria, citrate can be generated from acetyl CoA and oxaloacetate as part of the TCA cycle. However, under hypoxic conditions, some cells also produce citrate via reductive carboxylation of α-ketoglutarate (αKG) through the action of NADPH-dependent isocitrate dehydrogenases (IDH) (15-17)....

show abstract

Section: Discussionmentioning

confidence: 99%

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Yanagida

Knight

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

View full text Add to dashboard Cite

show abstract

“…In support of that concept, NAD + repletion with the NAD + precursor nicotinamide riboside (NR) prevented or reversed NAFLD in mice fed a high fat-high sucrose diet. NAD + protective effects were dependent on the induction of the aging-associated histone deacetylases, SIRT1 and SIRT3-mediated mitochondrial unfolded protein response (UPR mt ) 72 , triggering an adaptive pathway to increase hepatic beta-oxidation and mitochondrial complex content and activity. Thus, NAD + -induced SIRT1 activation regulates various cellular processes including energy metabolism, stress response and mitochondrial functions 68 .…”

Section: Molecular Mechanisms Of Hepatocyte Lipotoxicitymentioning

confidence: 99%

Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease

et al. 2016

View full text Add to dashboard Cite

The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity, respectively. A common denominator is metabolic derangement, especially in regards to intracellular energy homeostasis, which is brought on by glucose intolerance and insulin resistance in tissues. In this review, we highlight the lipids and carbohydrates that provoke hepatocyte injury and the mechanisms involved in lipotoxicity and glucotoxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment. Through upregulation of proteins involved in various pathways including PKR-like ER kinase (PERK), CCAAT/enhancer-binding homologous protein (CHOP), c-Jun NH2-terminal kinase-1 (JNK), Bcl-2 interacting mediator (BIM), p53 upregulated modulator of apoptosis (PUMA), and eventually caspases, hepatocytes in lipotoxic states ultimately undergo apoptosis. The protective role of certain lipids and possible targets for pharmacological therapy are explored. Finally, we discuss the role of high fructose and glucose diets in contributing to organelle impairment and poor glucose transport mechanisms, which perpetuate hyperglycemia and hyperlipidemia by shunting of excess carbohydrates into lipogenesis.

show abstract

“…In pre-diabetic mice NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis, while protecting against sensory neuropathy (Trammell et al, 2016). Additionally, NR was shown to prevent and reverse the development of nonalcoholic fatty liver disease (NAFLD) by inducing a SIRT1- and SIRT3-dependent mitochondrial unfolded protein response (Gariani et al, 2016). NR supplementation also increased mitochondrial NAD levels and improved mitochondria function of old mice (Gomes et al, 2013), and rejuvenated and prevented senescence of muscle stem cells in aged mice (Zhang et al, 2016).…”

Section: Interventions To Prevent Age-related Nad Declinementioning

confidence: 99%

NAD and the aging process: Role in life, death and everything in between

Chini

Tarragó

Chini

2017

Molecular and Cellular Endocrinology

154

179

View full text Add to dashboard Cite

Life as we know it cannot exist without the nucleotide nicotinamide adenine dinucleotide (NAD). From the simplest organism, such as bacteria, to the most complex multicellular organisms, NAD is a key cellular component. NAD is extremely abundant in most living cells and has traditionally been described to be a cofactor in electron transfer during oxidation-reduction reactions. In addition to participating in these reactions, NAD has also been shown to play a key role in cell signaling, regulating several pathways from intracellular calcium transients to the epigenetic status of chromatin. Thus, NAD is a molecule that provides an important link between signaling and metabolism, and serves as a key molecule in cellular metabolic sensoring pathways. Importantly, it has now been clearly demonstrated that cellular NAD levels decline during chronological aging. This decline appears to play a crucial role in the development of metabolic dysfunction and age-related diseases. In this review we will discuss the molecular mechanisms responsible for the decrease in NAD levels during aging. Since other reviews on this subject have been recently published, we will concentrate on presenting a critical appraisal of the current status of the literature and will highlight some controversial topics in the field. In particular, we will discuss the potential role of the NADase CD38 as a driver of age-related NAD decline.

show abstract

Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice

Cited by 299 publications

References 44 publications

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease

NAD and the aging process: Role in life, death and everything in between

Contact Info

Product

Resources

About