Abstract
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.
Highlights
In order to proliferate and survive, cells need to continuously obtain fatty acids (FFAs) to provide energy, support membrane synthesis, and participate in cellular signaling [1].Cells can obtain FFAs through external uptake or de novo synthesis and use theseFFAs to synthesize lipids, such as triglycerides and glycerophospholipids [2]
The results showed that magnesium isoglycyrrhizinate (MGIG) had a protective effect against palmitic acid (PA)-induced cytotoxicity in HepaRG
MGIG, they both decreased significantly and even recovered to normal levels. These results show that MGIG can inhibit the cellular uptake of saturated fatty acids to synthesize triglycerides and phospholipids, thereby inhibiting the formation of rigid and MS-DIAL lipidomics database, including about 4000 lipids in lipid subclasses; (B) Visual plot of the metabolic network of palmitic acid in the glycerophospholipid pathway in untreated cells, drawn using Cytoscape software (n = 5); (C) Visual plot of the changes in the content of differential lipids involved in the metabolic network of palmitic acid in cells administered 0.2 mM palmitic acid for h (n = 5); (D) Visual plot of the content changes in cells administered 0.2 mM palmitic
Summary
In order to proliferate and survive, cells need to continuously obtain fatty acids (FFAs) to provide energy, support membrane synthesis, and participate in cellular signaling [1].Cells can obtain FFAs through external uptake or de novo synthesis and use theseFFAs to synthesize lipids, such as triglycerides and glycerophospholipids [2]. In order to proliferate and survive, cells need to continuously obtain fatty acids (FFAs) to provide energy, support membrane synthesis, and participate in cellular signaling [1]. Abundant lipids in the body; most tissues can use the decomposition products of triglycerides to provide energy [4]. Glycerophospholipids, the most abundant phospholipids in the body, are some of the main lipid components of cell membranes, and participate in recognition and signal transduction on cell membranes [4,5]. The excessive accumulation of lipids and their intermediate products in nonadipose tissues causes metabolic abnormalities and cell death in a process known as lipotoxicity [6]. In nonalcoholic fatty liver disease (NAFLD), the lipotoxic apoptosis of hepatocytes is an important initial event in the diagnosis of the disease, and this phenomenon continues to occur during the development of the disease [9]
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