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. 2024 Apr 22;12(7):5100-5110.
doi: 10.1002/fsn3.4159. eCollection 2024 Jul.

Restoring energy metabolism by NAD+ supplement prevents alcohol-induced liver injury and boosts liver regeneration

Yao Liu  1   2 , Cheng Cheng  1   3 , Han Gao  1   4 , Xue-Jin Zhu  1   4 , Xian He  1 , Ming-Xi Zhou  1 , Yuan Gao  1 , Ya-Wen Lu  1 , Xin-Hua Song  1 , Xiao-He Xiao  5 , Jia-Bo Wang  1 , Chun-Jun Xu  2 , Zhi-Tao Ma  1
Affiliations

Restoring energy metabolism by NAD+ supplement prevents alcohol-induced liver injury and boosts liver regeneration

Yao Liu et al. Food Sci Nutr. .

Abstract

Our previous clinical metabolomics study illustrated that energy metabolism disorder is an underlying pathogenesis mechanism for the development of alcoholic liver disease (ALD). Supplementation of nicotinamide (NAM), the precursor of nicotinamide adenine dinucleotide (NAD+), may restore the energy metabolism homeostasis of ALD and thus serves as potential therapeutics to treat ALD. In this bedside-to-bench study, the protective effect of NAM against ALD was investigated by using the NIAAA mice model (chronic-plus-binge ethanol), and the liver regeneration boosting capability of NAM was evaluated by the partial hepatectomy mice model. Our results showed that NAM supplements not only protected the liver from alcohol-induced injury and improved alcohol-induced mitochondrial structure and function change, but also boosted liver regeneration in postpartial hepatectomy mice by increasing liver NAD+ content. These findings suggested that NAM, a water-soluble form of vitamin B3, can promote liver regeneration and improves liver function by alleviating alcohol-induced energy metabolism disorder.

Keywords: alcoholic liver disease; energy; liver regeneration; metabolism; mitochondria; nicotinamide.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

FIGURE 1
FIGURE 1
NAM alleviates hepatic steatosis in mice fed with chronic‐plus‐binge ethanol. Mice were treated with chronic‐plus‐binge ethanol feeding and NAM supplementation for 10 days. Representative images of mouse liver, H&E staining, and oil red O staining with 200 × magnification. NAM, nicotinamide.
FIGURE 2
FIGURE 2
NAM alleviates hepatic steatosis in mice fed with chronic‐plus‐binge ethanol. Mice were treated with chronic‐plus‐binge ethanol feeding and NAM supplementation for 16 days. (a) Serum AST levels. (b) Serum ALT levels. (c) Serum MDA levels. (d) Serum GSH levels. (e) Serum GGT levels. (f) Serum TG levels. (g) Western blot analysis of alcohol metabolic enzymes (CYP2E1, ADH1, and ALDH2) in mouse liver. (h) Western blot analysis of lipid metabolic regulators (SREBP‐1c and PPAR‐γ2) in mouse liver. (i) Western blot fold changes of control. Results were expressed as fold changes of control. Data are expressed as mean ± SEM. n = 6–9/group, *p < .05 compared with the CTRL group; **p < .01 compared with the CTRL group; # p < .05 compared with the EtOH group; ## p < .01 compared with the EtOH group. ADH1, alcohol dehydrogenase 1; ALDH2, aldehyde dehydrogenase 2; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CYP2E1, cytochrome P450 2E1; GGT, γ‐glutamyl transpeptidase; PGC‐1α, peroxisome proliferator‐activated receptor γ coactivator‐1α; PPAR‐γ2, peroxisome proliferator‐activated receptor γ2; MDA, malondialdehyde; SREBP‐1c, sterol regulatory element binding protein‐lc; TG, triglyceride.
FIGURE 3
FIGURE 3
NAM significantly improves alcohol‐induced NAD+ drain. (a) Liver NAD+ levels. (b) Western blot analysis of NAMPT in mouse liver. (c) Serum NAMPT levels. (d) Western blot fold changes of control. (e) Liver IL‐22 level. Data are expressed as mean ± SEM. n = 6–9/group, *p < .05 compared with the CTRL group; **p < .01 compared with the CTRL group; # p < .05 compared with the EtOH group; ## p < .01 compared with the EtOH group. NAD+, nicotinamide adenine dinucleotide; NAM, nicotinamide; NAMPT, nicotinamide phosphoribosyl transferase.
FIGURE 4
FIGURE 4
NAM improves the alcohol‐induced mitochondrial structure change. Representative liver electron micrographs. Chromatin (red arrow), nuclear membrane structure of the nucleus (purple arrow), intracytoplasmic lipid structure (blue arrow), intracytoplasmic mitochondrial membrane (yellow arrows), irregular cavity formed after suspected protein degradation (orange arrow), endoplasmic reticulum (green arrow), and intramitochondrial cristae (white arrow). NAM, nicotinamide.
FIGURE 5
FIGURE 5
NAM significantly improves alcohol‐induced mitochondrial dysfunction. (a) Western blot analysis of SDH, CS in mouse liver. (b) Western blot analysis of UCP2 in mouse liver. (c) Western blot fold changes of control. (d) Liver ATP levels. (e) Liver SDH activity. (f) Liver CS activity. (g) Liver GSH/GSSG ratio. (h) ROS relative multiple of control. Data are expressed as mean ± SEM. n = 6–9/group, *p < .05 compared with the CTRL group; **p < .01 compared with the CTRL group; # p < .05 compared with the EtOH group; ## p < .01 compared with the EtOH group. CS, citrate synthase; NAM, nicotinamide; SDH, succinate dehydrogenase; UCP2, uncoupling protein 2.
FIGURE 6
FIGURE 6
NAM motivates liver regeneration in NIAAA mice after PH. (a) Immunohistochemistry for Ki‐67 at the indicated time points. Black scale bars, 200 μm. (b) Serum NAD+ levels. (c) Serum AST and (d) ALT levels at the indicated time points following PH. Results were expressed as fold changes of control Data are expressed as mean ± SEM. n = 3–5/group, *p < .05 compared with the CTRL group; **p < .01 compared with the CTRL group; # p < .05 compared with the EtOH group; ## p < .01 compared with the EtOH group. ALT, alanine aminotransferase; AST, aspartate aminotransferase; NAD+, nicotinamide adenine dinucleotide; NAM, nicotinamide; PH, partial hepatectomy.
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