Nuclear Nicotinamide Adenine Dinucleotide Deficiency by Nmnat1 Deletion Impaired Hepatic Insulin Signaling, Mitochondrial Function, and Hepatokine Expression in Mice Fed a High-Fat Diet

Dong, Haibo; Guo, Wei; Yue, Ruichao; Sun, Xinguo; Zhou, Zhanxiang

doi:10.1016/j.labinv.2024.100329

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…Nmnat1 mutation in retinal tissues can significantly damage optical functions [ 29 ]. According to a recent study on liver-specific Nmnat1 CKO, mitochondrial dysfunction impairs insulin resistance [ 30 ]. Moreover, Nmnat1 knockdown increases the damage caused by respiratory infections [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

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Nmnat1 Deficiency Causes Mitoribosome Excess in Diabetic Nephropathy Mediated by Transcriptional Repressor HIC1

Hasegawa,

Tamaki,

Sakamaki

et al. 2024

IJMS

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Nicotinamide adenine dinucleotide (NAD) is involved in renal physiology and is synthesized by nicotinamide mononucleotide adenylyltransferase (NMNAT). NMNAT exists as three isoforms, namely, NMNAT1, NMNAT2, and NMNAT3, encoded by Nmnat1, Nmnat2, and Nmnat3, respectively. In diabetic nephropathy (DN), NAD levels decrease, aggravating renal fibrosis. Conversely, sodium–glucose cotransporter-2 inhibitors increase NAD levels, mitigating renal fibrosis. In this regard, renal NAD synthesis has recently gained attention. However, the renal role of Nmnat in DN remains uncertain. Therefore, we investigated the role of Nmnat by establishing genetically engineered mice. Among the three isoforms, NMNAT1 levels were markedly reduced in the proximal tubules (PTs) of db/db mice. We examined the phenotypic changes in PT-specific Nmnat1 conditional knockout (CKO) mice. In CKO mice, Nmnat1 expression in PTs was downregulated when the tubules exhibited albuminuria, peritubular type IV collagen deposition, and mitochondrial ribosome (mitoribosome) excess. In CKO mice, Nmnat1 deficiency-induced mitoribosome excess hindered mitoribosomal translation of mitochondrial inner membrane-associated oxidative phosphorylation complex I (CI), CIII, CIV, and CV proteins and mitoribosomal dysfunction. Furthermore, the expression of hypermethylated in cancer 1, a transcription repressor, was downregulated in CKO mice, causing mitoribosome excess. Nmnat1 overexpression preserved mitoribosomal function, suggesting its protective role in DN.

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Section: Discussionmentioning

confidence: 99%

“…We cloned and transfected the Hic1 expression vector and treated the HK2 cells with small interfering RNAs (siRNAs) targeting Nmnat1 (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA), as previously described [ 30 , 35 ]. For the negative control, siRNA for green fluorescent protein (5′-GGCTACGTCCAGCAGCGCACC-3′) mRNA was used.…”

Section: Methodsmentioning

confidence: 99%

Nmnat1 Deficiency Causes Mitoribosome Excess in Diabetic Nephropathy Mediated by Transcriptional Repressor HIC1

Hasegawa,

Tamaki,

Sakamaki

et al. 2024

IJMS

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“…Furthermore, NNMT gene knockout resulted in a significant reduction in adipogenesis. Dong et al demonstrated that knockdown of the Nmnat1 gene in hepatic cells leads to depletion of nuclear NAD + , thereby causing mitochondrial dysfunction ( Dong et al, 2024 ). NMNAT is an essential key enzyme in the NAD + salvage pathway.…”

Section: Study Progress Of Nnmt In Mets-related Diseasesmentioning

confidence: 99%

Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome

Sun,

Zhu,

et al. 2024

Front. Pharmacol.

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Metabolic syndrome (MetS) represents a constellation of metabolic abnormalities, typified by obesity, hypertension, hyperglycemia, and hyperlipidemia. It stems from intricate dysregulations in metabolic pathways governing energy and substrate metabolism. While comprehending the precise etiological mechanisms of MetS remains challenging, evidence underscores the pivotal roles of aberrations in lipid metabolism and insulin resistance (IR) in its pathogenesis. Notably, nicotinamide N-methyltransferase (NNMT) has recently surfaced as a promising therapeutic target for addressing MetS. Single nucleotide variants in the NNMT gene are significantly correlated with disturbances in energy metabolism, obesity, type 2 diabetes (T2D), hyperlipidemia, and hypertension. Elevated NNMT gene expression is notably observed in the liver and white adipose tissue (WAT) of individuals with diabetic mice, obesity, and rats afflicted with MetS. Knockdown of NNMT elicits heightened energy expenditure in adipose and hepatic tissues, mitigates lipid accumulation, and enhances insulin sensitivity. NNMT catalyzes the methylation of nicotinamide (NAM) using S-adenosyl-methionine (SAM) as the donor methyl group, resulting in the formation of S-adenosyl-l-homocysteine (SAH) and methylnicotinamide (MNAM). This enzymatic process results in the depletion of NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and the generation of SAH, a precursor of homocysteine (Hcy). Consequently, this cascade leads to reduced NAD+ levels and elevated Hcy levels, implicating NNMT in the pathogenesis of MetS. Moreover, experimental studies employing RNA interference (RNAi) strategies and small molecule inhibitors targeting NNMT have underscored its potential as a therapeutic target for preventing or treating MetS-related diseases. Nonetheless, the precise mechanistic underpinnings remain elusive, and as of yet, clinical trials focusing on NNMT have not been documented. Therefore, further investigations are warranted to elucidate the intricate roles of NNMT in MetS and to develop targeted therapeutic interventions.

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Exploring new mechanisms of Imeglimin in diabetes treatment: Amelioration of mitochondrial dysfunction

Li,

Lou,

Liu

et al. 2024

Biomedicine & Pharmacotherapy

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Nuclear Nicotinamide Adenine Dinucleotide Deficiency by Nmnat1 Deletion Impaired Hepatic Insulin Signaling, Mitochondrial Function, and Hepatokine Expression in Mice Fed a High-Fat Diet

Cited by 3 publications

References 44 publications

Nmnat1 Deficiency Causes Mitoribosome Excess in Diabetic Nephropathy Mediated by Transcriptional Repressor HIC1

Nmnat1 Deficiency Causes Mitoribosome Excess in Diabetic Nephropathy Mediated by Transcriptional Repressor HIC1

Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome

Exploring new mechanisms of Imeglimin in diabetes treatment: Amelioration of mitochondrial dysfunction

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