2. Academic Validation
  3. Alternative pathway of bile acid biosynthesis contributes to ameliorate NASH after induction of NAMPT/NAD+/SIRT1 axis

Alternative pathway of bile acid biosynthesis contributes to ameliorate NASH after induction of NAMPT/NAD+/SIRT1 axis

  • Biomed Pharmacother. 2023 Jun 12;164:114987. doi: 10.1016/j.biopha.2023.114987.
Na Yang 1,  Runbin Sun 2,  Xiaoli Zhang 3,  Jing Wang 4,  Lulu Wang 5,  Huaijun Zhu 5,  Man Yuan 6,  Yifan Xu 6,  Chun Ge 7,  Jun He 8,  Min Wang 9
Affiliations

Affiliations

  • 1 Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu, China; Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China.
  • 2 Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu, China.
  • 3 Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China.
  • 4 Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu, China.
  • 5 Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu, China.
  • 6 Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu, China.
  • 7 Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu, China. Electronic address: gechun@stu.cpu.edu.cn.
  • 8 Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China. Electronic address: hej@njucm.edu.cn.
  • 9 Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu, China; Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China. Electronic address: 220110809@seu.edu.cn.
PMID: 37315437 DOI: 10.1016/j.biopha.2023.114987
Abstract

Non-alcoholic steatohepatitis (NASH) is emerging as a serious liver disorder characterized by hepatic steatosis and liver inflammation. Nicotinamide adenine dinucleotide (NAD+) and NAD+-dependent deacetylase, SIRT1, play important roles in lipid metabolism in non-alcoholic fatty liver disease (NAFLD). However, their effects on liver inflammation and homeostasis of bile acids (BAs), the extensively proved pathophysiological actors in NASH, have not been fully understood. NASH animal model was induced by a methionine-choline-deficient (MCD) diet in C57BL/6J mice and intraperitoneally injected with NAD+ precursor, an agonist of upstream rate-limiting Enzyme NAMPT or downstream SIRT1, or their vehicle Solvents. Free fatty acid (FFA) was applied to HepG2 cells to construct the cell model. Induction of NAMPT/NAD+/SIRT1 axis could remarkably alleviate the aggravated inflammation in the liver of NASH mice, accompanied by decreased levels of total BAs throughout the enterohepatic system and a switch of BA synthesis from the classic pathway to the alternative pathway, resulting in less production of pro-inflammatory 12-OH BAs. The expressions of key Enzymes including cyp7a1, cyp8b1, cyp27a1 and cyp7b1 in BA synthesis were significantly modulated after NAMPT/NAD+/SIRT1 axis induction in both animal and cell models. The levels of pro-inflammatory cytokines in liver were significantly negatively correlated with the intermediates in NAD+ metabolism, which may also be related to their regulation on BA homeostasis. Our results indicated that induction of NAMPT/NAD+/SIRT1 axis may be a potential therapeutic strategy for NASH or its complications related with BAs.

Keywords

Bile acids; NAD(+); NAMPT; NASH; SIRT1.

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