NAD⁺-boosting therapy alleviates nonalcoholic fatty liver disease via stimulating a novel exerkine Fndc5/irisin

Abstract

Rationale: Nicotinamide adenine dinucleotide + (NAD + )-boosting therapy has emerged as a promising strategy to treat various health disorders, while the underlying molecular mechanisms are not fully understood. Here, we investigated the involvement of fibronectin type III domain containing 5 (Fndc5) or irisin, which is a novel exercise-linked hormone, in the development and progression of nonalcoholic fatty liver disease (NAFLD). Methods: NAD + -boosting therapy was achieved by administrating of nicotinamide riboside (NR) in human and mice. The Fndc5/irisin levels in tissues and blood were measured in NR-treated mice or human volunteers. The therapeutic action of NR against NAFLD pathologies induced by high-fat diet (HFD) or methionine/choline-deficient diet (MCD) were compared between wild-type (WT) and Fndc5 -/- mice. Recombinant Fndc5/irisin was infused to NALFD mice via osmotic minipump to test the therapeutic action of Fndc5/irisin. Various biomedical experiments were conducted in vivo and in vitro to know the molecular mechanisms underlying the stimulation of Fndc5/irisin by NR treatment. Results: NR treatment elevated plasma level of Fndc5/irisin in mice and human volunteers. NR treatment also increased Fndc5 expression in skeletal muscle, adipose and liver tissues in mice. In HFD-induced NAFLD mice model, NR displayed remarkable therapeutic effects on body weight gain, hepatic steatosis, steatohepatitis, insulin resistance, mitochondrial dysfunction, apoptosis and fibrosis; however, these actions of NR were compromised in Fndc5 -/- mice. Chronic infusion of recombinant Fndc5/irisin alleviated the NAFLD pathological phenotypes in MCD-induced NAFLD mice model. Mechanistically, NR reduced the lipid stress-triggered ubiquitination of Fndc5, which increased Fndc5 protein stability and thus enhanced Fndc5 protein level. Using shRNA-mediated knockdown screening, we found that NAD + -dependent deacetylase SIRT2, rather than other sirtuins, interacts with Fndc5 to decrease Fndc5 acetylation, which reduces Fndc5 ubiquitination and stabilize it. Treatment of AGK2, a selective inhibitor of SIRT2, blocked the therapeutic action of NR against NAFLD pathologies and NR-induced Fndc5 deubiquitination/deacetylation. At last, we identified that the lysine sites K127/131 and K185/187/189 of Fndc5 may contribute to the SIRT2-dependent deacetylation and deubiquitination of Fndc5. Conclusions: The findings from this research for the first time demonstrate that NAD + -boosting therapy reverses NAFLD by regulating SIRT2-deppendent Fndc5 deacetylation and deubiquitination, which results in a stimulation of Fndc5/irisin, a novel exerkine. These results suggest that Fndc5/irisin may be a potential nexus betw...

The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease

“…In humans and mice with NAFLD, a reduced cellular availability of NAD+ resulted in higher fat content and alimentary NAD+ supplementation reversed the effect [ 61 , 62 ]. Low NAD+ levels may activate p53, thereby inducing cell cycle arrest [ 63 ].…”

Selective targeting of CD38 hydrolase and cyclase activity as an approach to immunostimulation

“…However, CD38 inhibition could also be exploited in the treatment of other diseases resulting from depletion of NAD + and/or over production of ADO. Decreases in NAD + levels are associated with various metabolic diseases (diabetes, obesity, dyslipidemia and nonalcoholic fatty liver) 48,49 and in aging. [50][51][52] It also plays a major role in the immune response to infectious disease 53 including COVID-19.…”

Antioxidant Effects of Irisin in Liver Diseases: Mechanistic Insights

“…Therefore, the maintenance of normal serum irisin concentrations would also be important for irisin to exert antioxidant effects in liver disease. Furthermore, Li and colleagues found that under lipid stress, the acetylation and ubiquitination of the Fndc5 protein were dramatically strengthened, which accelerated Fndc5 degradation and consequently decreased the serum irisin concentration [89]. Based on this finding, we hypothesized that deacetylation and deubiquitination of Fndc5 would reverse the irisin level reduction.…”

“…It was speculated that SIRT2 was the deacetylase of Fndc5. Moreover, Li et al found that the K127/131 and K185/187/189 sites of Fndc5 were essential for the deacetylation activity of SIRT2 [89] (Figure 2). Lantier and colleagues demonstrated that the depletion of SIRT2 would cause abnormal mitochondrial biosynthesis, which might negatively influence the antioxidant effect of irisin [90].…”