Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic Abnormalities
The excessive accumulation of lipids in hepatocytes induces a type of cytotoxicity called hepatic lipotoxicity, which is a fundamental contributor to liver metabolic diseases (such as NAFLD). Magnesium isoglycyrrhizinate (MGIG), a magnesium salt of the stereoisomer of natural glycyrrhizic acid, is w...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2021-05-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/22/11/5884 |
id |
doaj-3b05757f812541a5912b034325ac5da3 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Li Lu Kun Hao Yu Hong Jie Liu Jinwei Zhu Wenjiao Jiang Zheying Zhu Guangji Wang Ying Peng |
spellingShingle |
Li Lu Kun Hao Yu Hong Jie Liu Jinwei Zhu Wenjiao Jiang Zheying Zhu Guangji Wang Ying Peng Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic Abnormalities International Journal of Molecular Sciences magnesium isoglycyrrhizinate palmitic acid hepatic lipotoxicity metabonomics lipidomics |
author_facet |
Li Lu Kun Hao Yu Hong Jie Liu Jinwei Zhu Wenjiao Jiang Zheying Zhu Guangji Wang Ying Peng |
author_sort |
Li Lu |
title |
Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic Abnormalities |
title_short |
Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic Abnormalities |
title_full |
Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic Abnormalities |
title_fullStr |
Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic Abnormalities |
title_full_unstemmed |
Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic Abnormalities |
title_sort |
magnesium isoglycyrrhizinate reduces hepatic lipotoxicity through regulating metabolic abnormalities |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-05-01 |
description |
The excessive accumulation of lipids in hepatocytes induces a type of cytotoxicity called hepatic lipotoxicity, which is a fundamental contributor to liver metabolic diseases (such as NAFLD). Magnesium isoglycyrrhizinate (MGIG), a magnesium salt of the stereoisomer of natural glycyrrhizic acid, is widely used as a safe and effective liver protectant. However, the mechanism by which MGIG protects against NAFLD remains unknown. Based on the significant correlation between NAFLD and the reprogramming of liver metabolism, we aimed to explore the beneficial effects of MGIG from a metabolic viewpoint in this paper. We treated HepaRG cells with palmitic acid (PA, a saturated fatty acid of C16:0) to induce lipotoxicity and then evaluated the antagonistic effect of MGIG on lipotoxicity by investigating the cell survival rate, DNA proliferation rate, organelle damage, and endoplasmic reticulum stress (ERS). Metabolomics, lipidomics, and isotope tracing were used to investigate changes in the metabolite profile, lipid profile, and lipid flux in HepaRG cells under different intervention conditions. The results showed that MGIG can indeed protect hepatocytes against PA-induced cytotoxicity and ERS. In response to the metabolic abnormality of lipotoxicity, MGIG curtailed the metabolic activation of lipids induced by PA. The content of total lipids and saturated lipids containing C16:0 chains increased significantly after PA stimulation and then decreased significantly or even returned to normal levels after MGIG intervention. Lipidomic data show that glycerides and glycerophospholipids were the two most affected lipids. For excessive lipid accumulation in hepatocytes, MGIG can downregulate the expression of the metabolic enzymes (GPATs and DAGTs) involved in triglyceride biosynthesis. In conclusion, MGIG has a positive regulatory effect on the metabolic disorders that occur in hepatocytes under lipotoxicity, and the main mechanisms of this effect are in lipid metabolism, including reducing the total lipid content, reducing lipid saturation, inhibiting glyceride and glycerophospholipid metabolism, and downregulating the expression of metabolic enzymes in lipid synthesis. |
topic |
magnesium isoglycyrrhizinate palmitic acid hepatic lipotoxicity metabonomics lipidomics |
url |
https://www.mdpi.com/1422-0067/22/11/5884 |
work_keys_str_mv |
AT lilu magnesiumisoglycyrrhizinatereduceshepaticlipotoxicitythroughregulatingmetabolicabnormalities AT kunhao magnesiumisoglycyrrhizinatereduceshepaticlipotoxicitythroughregulatingmetabolicabnormalities AT yuhong magnesiumisoglycyrrhizinatereduceshepaticlipotoxicitythroughregulatingmetabolicabnormalities AT jieliu magnesiumisoglycyrrhizinatereduceshepaticlipotoxicitythroughregulatingmetabolicabnormalities AT jinweizhu magnesiumisoglycyrrhizinatereduceshepaticlipotoxicitythroughregulatingmetabolicabnormalities AT wenjiaojiang magnesiumisoglycyrrhizinatereduceshepaticlipotoxicitythroughregulatingmetabolicabnormalities AT zheyingzhu magnesiumisoglycyrrhizinatereduceshepaticlipotoxicitythroughregulatingmetabolicabnormalities AT guangjiwang magnesiumisoglycyrrhizinatereduceshepaticlipotoxicitythroughregulatingmetabolicabnormalities AT yingpeng magnesiumisoglycyrrhizinatereduceshepaticlipotoxicitythroughregulatingmetabolicabnormalities |
_version_ |
1721411772097757184 |
spelling |
doaj-3b05757f812541a5912b034325ac5da32021-06-01T01:42:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-01225884588410.3390/ijms22115884Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic AbnormalitiesLi Lu0Kun Hao1Yu Hong2Jie Liu3Jinwei Zhu4Wenjiao Jiang5Zheying Zhu6Guangji Wang7Ying Peng8Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, ChinaKey Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, ChinaKey Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, ChinaKey Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, ChinaKey Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, ChinaKey Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, ChinaDivision of Molecular Therapeutics & Formulation, School of Pharmacy, University Park Campus, The University of Nottingham, Nottingham NG7 2RD, UKKey Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, ChinaKey Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, ChinaThe excessive accumulation of lipids in hepatocytes induces a type of cytotoxicity called hepatic lipotoxicity, which is a fundamental contributor to liver metabolic diseases (such as NAFLD). Magnesium isoglycyrrhizinate (MGIG), a magnesium salt of the stereoisomer of natural glycyrrhizic acid, is widely used as a safe and effective liver protectant. However, the mechanism by which MGIG protects against NAFLD remains unknown. Based on the significant correlation between NAFLD and the reprogramming of liver metabolism, we aimed to explore the beneficial effects of MGIG from a metabolic viewpoint in this paper. We treated HepaRG cells with palmitic acid (PA, a saturated fatty acid of C16:0) to induce lipotoxicity and then evaluated the antagonistic effect of MGIG on lipotoxicity by investigating the cell survival rate, DNA proliferation rate, organelle damage, and endoplasmic reticulum stress (ERS). Metabolomics, lipidomics, and isotope tracing were used to investigate changes in the metabolite profile, lipid profile, and lipid flux in HepaRG cells under different intervention conditions. The results showed that MGIG can indeed protect hepatocytes against PA-induced cytotoxicity and ERS. In response to the metabolic abnormality of lipotoxicity, MGIG curtailed the metabolic activation of lipids induced by PA. The content of total lipids and saturated lipids containing C16:0 chains increased significantly after PA stimulation and then decreased significantly or even returned to normal levels after MGIG intervention. Lipidomic data show that glycerides and glycerophospholipids were the two most affected lipids. For excessive lipid accumulation in hepatocytes, MGIG can downregulate the expression of the metabolic enzymes (GPATs and DAGTs) involved in triglyceride biosynthesis. In conclusion, MGIG has a positive regulatory effect on the metabolic disorders that occur in hepatocytes under lipotoxicity, and the main mechanisms of this effect are in lipid metabolism, including reducing the total lipid content, reducing lipid saturation, inhibiting glyceride and glycerophospholipid metabolism, and downregulating the expression of metabolic enzymes in lipid synthesis.https://www.mdpi.com/1422-0067/22/11/5884magnesium isoglycyrrhizinatepalmitic acidhepatic lipotoxicitymetabonomicslipidomics |