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Discovery of New Inducements for Fatty Liver | Wang Zhao Team of Our Hospital Published a Review Article on Carbohydrate Deterioration of Fatty Liver
Recently, Wang Zhao, director of the Institute of Biomedicine and Equipment of our hospital, was invited to publish a review paper entitled "Carbohydrate Worsening Fatty Liver by Activating Inflammatory Response" (Carbohydrates deteriorate fatty liver by activating the inflammatory response) online in the internationally renowned academic journal Nutrition Research Review (Nutrition Research Reviews). Details are as follows.
Recently, the Wang Zhao research group of Tsinghua University's School of Pharmacy was invited to publish an online review paper entitled "Carbohydrates worsen fatty liver through activation of inflammatory response" (Carbohydrates deteriorate fatty liver by activating the inflammatory response) in the nutrition research review (Nutrition Research Reviews), which systematically summarized the development history, classification and metabolic process of carbohydrates. Through collation and analysis of previously published literature data, it is concluded that starch carbohydrates are directly related to the level of inflammation in the body; the key factors and related pathways that induce liver inflammation are summarized; the possibility of mTORC1 regulating carbohydrate-induced inflammation and lipid accumulation is proposed, and the future research direction of carbohydrates affecting liver lipid metabolism is discussed and prospected.
Carbohydrate fatty liver "chronic killer"
Fatty liver is a disease of abnormal liver lipid metabolism characterized by the accumulation of lipids in the liver. It affects more than 1/4 of the world's population. In my country, the prevalence rate has reached nearly 30%. It is currently one of the most serious public health problems.
Dietary adjustment is currently recognized as the most economical and effective way to alleviate fatty liver.
In the past, excessive intake of a high-fat diet was considered to be the main cause of fatty liver. However, in recent years, a number of population studies have shown that the intake of carbohydrates, especially free sugars, plays an important role in inducing fatty liver and causing its further deterioration. In addition, carbohydrates are the main component of daily staple food, and the impact is persistent.
However, the effect of starch carbohydrates on fatty liver and the mechanism of carbohydrate regulation of liver lipid metabolism have not been systematically described.
Correlation analysis Carbohydrates may regulate liver lipids through inflammation
By searching for relevant reports in PubMed, Clinicalkey, Web of Science, and Scopus databases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma were selected to represent inflammatory levels, triglycerides (TG) and total cholesterol (TC) in plasma represented lipid levels, and carbohydrates were divided into total carbohydrates, free sugars, and starch carbohydrates, and correlation analysis was performed respectively.
Experimental results are obtained:
① Starch carbohydrates were positively correlated with AST and ALT, while free sugars were positively correlated with AST, but not with ALT. Starch carbohydrates showed a higher correlation with AST than free sugars.
②There was no correlation between total carbohydrate, free sugar or starch carbohydrate and lipid index TG and TC.
③ TG was positively correlated with AST and ALT.
Combined with previous reports and previous studies of the research group, high carbohydrate intake will aggravate the accumulation of lipid in the liver and systemic inflammation, suggesting the possibility of carbohydrate regulation of liver lipid through inflammation.
Figure 1 The main pathways and regulatory factors leading to liver inflammation
Pathways and key factors in inducing liver inflammation
As an important nuclear transcription factor, NF-κB plays an important role in the body's inflammatory response and immune response, and it is also the most reported factor inducing liver inflammation in current studies.
When the cells are stimulated, IκB kinase is degraded by phosphorylation/ubiquitination, releasing NF-κB dimer, transferring NF-κB into the nucleus, and promoting the transcription and expression of downstream inflammatory factors by binding to the target gene promoter, thus causing liver inflammation.
Current reports, such as PARP-1/PPARα/SIRT1 pathway, MAPK pathway, TLR4 signaling pathway, etc., all induce liver inflammation by activating NF-κB or cooperating with NF-κB. High fructose-induced intrahepatic inflammation is also due to increased uric acid levels and NF-κB activation; similarly, the PI3K-AKT pathway has been reported to regulate NF-κB expression.
In addition, reactive oxygen species, miRNAs, endoplasmic reticulum stress, etc., affect the expression and release of inflammatory factors by affecting MAPK, macrophages, SIRT1 and so on.
In addition, intestinal microflora can change intestinal permeability, affect intestinal metabolites, participate in immunity, regulate inflammation and release of inflammatory factors by remodeling intestinal microenvironment.
In addition, the disorder of other tissues and organs will also affect the inflammation level of the liver. For example, after the adipose tissue is damaged, a large number of fatty acids and inflammatory factors secreted can be transmitted to the liver through the blood circulation, thus causing inflammatory damage.
mTORC1 or as a key factor in the regulation of carbohydrate-induced inflammation
Figure 2 High carbohydrate leads to inflammation through the mtorc1 pathway and further regulates lipid production
Based on the current studies and our analysis, carbohydrates induce inflammation mainly through the NF-κB and mTORC1 pathways.
Carbohydrates are digested into monosaccharides in the intestine and enter cells through GLUT4, metabolized to citrate through the TCA cycle, and then synthesized fatty acids through the de novo lipid synthesis pathway and activated NF-κB, inducing the production of a large number of inflammatory cytokines.
In addition, carbohydrates further induce the release of inflammatory factors by affecting intracellular ROS and NO levels.
At the same time, the mTORC1 pathway activated by PI3K/AKT can also lead to an increase in the level of inflammation and the content of neutrophils in the liver, which together lead to an increase in the level of inflammation in the liver.
In addition, mTORC1 affects the transcription of nuclear lipid synthesis-related genes SREBP and PPARα through S6K1 and SK62, thereby promoting lipid synthesis and inhibiting fatty acid oxidation, leading to the formation of liver lipid deposition and fatty liver.
In this paper, the most common and easily ingested nutrients in life, carbohydrates, especially starch carbohydrates, are discussed in detail. By screening suitable clinical data from nearly 7000 articles, a significant positive correlation between carbohydrates and inflammation is analyzed, and the inference that carbohydrates intervene in liver lipid content in an indirect way is proposed. According to the current research reports, the possible role of mTORC1 in the regulation of carbohydrate-induced fatty liver is proposed, which provides new ideas for future research on glucose and lipid metabolism.
Professor Wang Zhao from the School of Pharmacy of Tsinghua University is the corresponding author of this article, and Gao Yuqi, a doctoral student in Wang Zhao's group, is the first author of this article. Laboratory members Hua Rui and Hu Kaiqiang participated in the work of this paper. This study was supported and funded by the National Natural Science Foundation of China (81871095), the Key R & D Program of the Ministry of Science and Technology (2018YFC2000304), the Overseas Key R & D Program (2016YFE113700), and the High-Precision Innovation Center for Structural Biology of Tsinghua University.
Institute of Biomedicine and Equipment
The Institute of Biomedicine and Equipment was established in 2016 with Professor Wang Zhao as its director. The team is committed to in-depth research in many fields such as life science, biomedicine, medical equipment, bio-related fluid mechanics and mechanical design, food safety and nutrition, etc. It also focuses on the development and application of ECMO blood pump, brain-strengthening instrument, sleep aid series products, household caries risk prediction and evaluation system, caries prevention ready-to-eat nutritious food, fruit and preservation of fruits and vegetable preservation, at the same time, it has obtained a number of related patents.
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