Short-term high salt intake impairs hepatic mitochondrial bioenergetics and biosynthesis in SIRT3 knockout mice

Abstract

High salt intake (HS) is an important factor in the development of many metabolic diseases. The liver is the metabolic center in the body. However, the effect of short-term HS on the liver mitochondria and its mechanism are still unclear. In this study, we investigated the effects of short-term HS on liver mitochondrial function. We found that HS reduced Sirtuin3 (SIRT3) protein level, increasing protein carbonylation in mice liver. HS intake decreased ATP production, mitochondrial transcription factor A (TFAM), and complex I level. SIRT3 knockout (SKO) mice exhibited similar results with HS-treated wild-type mice but with a less extent of carbonylation and ATP reduction. Our study shows that short-term HS led to increased hepatic oxidative state, impaired mitochondrial biosynthesis, and bioenergetics. HS-treated mice could still maintain hepatic glucose homeostasis by compensatory activation of Adenosine 5′-monophosphate-activated protein kinase (AMPK). However, in HS-treated SKO mice, AMPK was not activated, instead, the glycogen synthase activity increased, which caused an exceptionally increased glycogen accumulation. This study provides evidence that short-term HS intake could cause the early hepatic metabolic changes, highlighting the importance of controlling salt intake especially in those patients with defects in SIRT3.

Highlights

1. High salt intake down-regulates SIRT3 protein level and increases oxidation.

2. High salt intake activates AMPK via AMP-dependent pathway.

3. High salt intake impairs energy metabolism.

4. High salt combined with SIRT3 knockout results in glycogen accumulation.

Keywords:

• AMPK
• glucose metabolism
• high salt
• mitochondria
• ROS
• SIRT3

Acknowledgments

The authors are sincerely grateful to Xiaodong Zhang from Chengdu HitGen Ltd. for his proofreading and editing of the manuscript. The authors thank Ms. Hongyang Gao for her assistance in experiments. The authors are also indebted to Prof. Weili Shen from Ruijin Hospital, Shanghai Jiaotong University for the animal model.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China [grants 31270901, 30970684, 31770916], the project for by tenth scientific and technical innovation project of SHUTCM School of Public Health, Shanghai University of Traditional Chinese Medicine, and Project of State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital [2017].