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Secrets of Liver Regeneration: The Role of NAD+
  • 2023-11-28
  • admin

The liver, a powerhouse of regeneration among mammalian organs, possesses the incredible ability to fully renew itself in less than 30% of its original volume. This remarkable regenerative capacity becomes a crucial lifeline in the face of liver trauma, exposure to toxins, or surgical tumor removal. The recovery of liver function is intricately linked to an increase in the energy required for the restoration of liver mass. However, the exact mechanisms governing the liver's response to both acute and chronic injuries, as well as the pathways controlling its regenerative capabilities, have long remained elusive. So, what substances hold sway over liver regeneration?


Recent research has shed light on a fascinating aspect: during the initial stages of liver regeneration, there's a temporary dip in NAD (nicotinamide adenine dinucleotide) levels. NAD serves as a co-factor for glycolysis and mitochondrial respiration, and numerous enzymes within cells depend on NAD for their signaling functions. A shortage of NAD in damaged livers could potentially impede cellular energy and signal transduction, putting the brakes on liver regeneration. Additionally, a deficiency of NAD in a healthy liver might hamper fatty acid oxidation, contributing to lipid degeneration—a key feature of liver regeneration. So, how does this fluctuation in NAD concentration impact the speed of liver regeneration?


To unravel this mystery, researchers conducted partial liver resection in mice. The findings were intriguing: the availability of NAD indeed emerged as a limiting factor in liver regeneration. Mice given orally administered NAD precursors showed a notable increase in the replication speed of liver cells, signifying a significant improvement in liver mass. In the control group, comprising untreated mice, no alterations in liver size were discerned. Furthermore, mice supplemented with NAD precursors displayed diminished characteristics of liver fat degeneration, indicating that NAD not only propels liver regeneration but also ameliorates lipid changes.


A deeper dive into the interplay between NAD, lipid metabolism, and liver cell proliferation revealed a robust positive correlation between liver cell proliferation and liver NAD levels. Conversely, there was a negative correlation with liver triglyceride levels. This suggests an optimal NAD level is requisite to furnish energy for cell growth and division through lipid oxidation. Post liver resection, a rapid decline in cellular energy adenosine triphosphate (ATP) levels is reported. NAD precursor treatment significantly facilitated the recovery of ATP concentrations during liver regeneration, aligning with the hypothesis that optimal NAD levels are crucial to promoting lipid utilization as a fuel source. Moreover, ATP levels exhibited a positive correlation with NAD and liver cell proliferation, suggesting that NAD and its precursors can alleviate the energy stress induced by continuous liver regeneration. Thus, strategies to boost liver NAD levels may play a pivotal role in the self-repair of liver cells following damage or toxicity.


In recent years, the incidence of fatty liver disease has been on the rise, affecting individuals at increasingly younger ages. Fatty liver disease poses a significant threat to human health, ranking as the second-largest liver disease after viral hepatitis and demanding our attention.


Researchers found that the expression of NRK1 in the livers of mice subjected to a high-fat diet or aging significantly decreased. Elevating NRK1 levels proved effective in increasing liver NAD+ levels, reducing liver fat degeneration, and improving glucose tolerance and insulin sensitivity. This suggests that NRK1 enhances fatty liver by upregulating NAD+ levels. Can supplementing nicotinamide mononucleotide (NMN) to upregulate NAD+ improve fatty liver? Scientists discovered that slow NMN supplementation effectively enhanced liver glucose processing, reduced oxidative stress, prevented diet-induced liver fat accumulation in obese mice, and improved glucose metabolism and redox status in the liver. In mice on a high-fat diet, the effects of NMN were more pronounced than in normal mice, hinting at NMN's potential in treating obesity and related diseases.


NMN supplementation effectively enhanced liver glucose processing, reduced oxidative stress

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Enzymes in the NAD+ signaling pathway are known to shield the liver from the effects of fat accumulation, fibrosis, and insulin resistance—factors tied to the onset of fatty liver disease.


NAMPT plays a pivotal regulatory role in the development of high-fat diet-induced fatty liver disease: inhibiting NAMPT exacerbates liver fat degeneration, while overexpressing NAMPT significantly ameliorates liver lipid accumulation. This regulatory effect operates through a cascade of events, including "inhibition of NAMPT → reduction of NAD+ → inhibition of SIRT1 → weakening of SREBP1 deacetylation → reduced SREBP1 activity → upregulation of FASN and ACC expression."


SIRT1 and its downstream targets PGC-1a, PSK9, and SREBP1 play a crucial role in maintaining mitochondrial function, cholesterol transport, and fatty acid homeostasis. SIRT2 controls gluconeogenesis by deacetylating phosphoenolpyruvate carboxykinase. SIRT3 regulates OXPHOS, fatty acid oxidation, ketone production, and antioxidant stress. SIRT6 governs gluconeogenesis.


Given the significance of these pathways in the liver, maintaining NAD+ levels is indispensable for sustaining organ function. Under normal circumstances, NAMPT levels decrease, and CD38 levels increase due to obesity and aging, resulting in a twofold reduction in steady-state NAD+ levels by middle age.


Elevating NAD+ levels to match those of youth proves markedly effective in preventing and treating obesity, alcoholic fatty liver disease, and non-alcoholic steatohepatitis (NASH). Additionally, it improves glucose homeostasis and mitigates mitochondrial dysfunction, fostering overall liver health, enhancing regenerative capacity, and shielding the liver from toxic damage. The key lies in understanding the intricate dance of NAD+ within the liver—a dance that holds the promise of unlocking new avenues for liver health and regeneration.



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