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Liver is an important metabolic organ, which controls lipid, glucose and energy metabolism. The disorder of liver lipid metabolism is often associated with fatty liver, including nonalcoholic fatty liver (NAFLD), alcoholic fatty liver (AFLD) and hyperlipidemia. Studies have shown that hormones, transcription factors and inflammatory cytokines can lead to dyslipidemia and fatty liver. At the same time, many natural drugs have been proved to be effective in the treatment of fatty liver and metabolic diseases. Based on this, Professor Zhou Huiping of Virginia Federal University and Professor Wu Xudong of Nanjing University published the article "fatty liver diseases, mechanisms, and potential therapeutic plant medicines" in the third issue of CJNM, summarizing the pathological mechanism of fatty liver and related natural drugs.
hormone
Hormone regulatory network is complex, but it is very important for liver lipid metabolism. The liver also plays an important role in regulating hormone activation, transport and metabolism. Insulin is the most important anabolic hormone, which plays a key role in controlling carbohydrate and lipid metabolism. It also has a significant impact on protein and mineral metabolism. Insulin plays a role by activating cell surface receptor insulin receptor (IR). IR is a kind of tyrosine kinase, which can automatically phosphorylate the β subunit in cells, leading to the activation of IR. Activated IR further phosphorylates downstream intracellular targets and leads to subsequent biological reactions. Insulin mediated activation of phosphatidylinositol 3-kinase (PI3K) - Akt pathway plays an important role in liver glycolipid metabolism by stimulating glycogen synthesis to store glucose, promoting fatty acid synthesis and lipoprotein formation. Several important targets of PI3K / Akt, such as mTORC1, FOXO, srebp1c, ChREBP and GSK, not only regulate glucose and fat metabolism, but also cell growth.
The levels of thyroid hormone and lipid metabolism are very important for liver lipid metabolism. In the classical mechanism, th interacts with th receptor (THR) as a ligand dependent transcription factor, regulating lipid metabolism. There are two subtypes of threonine receptor, threonine α and threonine β. Threonine β is the main subtype of liver expression. Circulating free fatty acids (FFAs) are the main lipid sources of the liver, and they can be utilized by protein transporters such as fatty acid transferase, liver fatty acid binding protein and fatty acid transporter family. These fatty acid uptake proteins can be positively induced by peroxisome proliferator activated receptor (PPAR) at the transcription level and cross talk with THRs. Recent studies have shown that THRs may also regulate fatty acid transporters. It has been reported that liver uptake of triglyceride derived free fatty acids decreased in hypothyroid rats and increased in hyperthyroid rats. These two key enzymes, acetyl CoA carboxylase (ACC), are directly regulated by ths to promote adipogenesis.
In addition, th can also promote SREBP-1 protein level through MAPK / ERK and PI3K / Akt pathways, thus affecting various lipogenic genes at the transcription level. Th can also induce the expression of ChREBP and liver X receptor genes, both of which play an important role in liver adipogenesis. Liver cytoplasmic lipase mainly includes liver lipase and triglyceride lipase, which can lead to the utilization and β - oxidation of stored triglycerides. These lipases are regulated by state. The results showed that th signal in liver decreased significantly in hypothyroid mice, accompanied by the inhibition of lipolysis in adipose tissue. A recent study has shown that there is a relationship between th and lipophagocyticity. In this process, neutral lipid droplets are digested by autolysosomes, releasing free fatty acids for mitochondrial fat oxidation.
transcription factor
The lipid metabolism of the liver is regulated at both transcription and post transcription levels. A large number of transcription factors have been identified. Sirts are a group of highly conserved NAD + dependent deacetylases, also known as ADP ribosyltransferases, which contain seven sirt1-7 homologous genes in mammals. SIRT plays a key role in many biological processes, such as energy metabolism, tumor progression, DNA repair and inflammation. SIRT1, as the most widely studied member of SIRT family, plays a beneficial role in regulating liver lipid metabolism. Loss of liver specific SIRT1 using Al CRE (SIRT1 LKO) can lead to liver lipid accumulation and fatty liver. In contrast, mice with moderate overexpression of SIRT1 were protected from lipid-induced inflammation and liver steatosis. Recent studies have elucidated the role of sirit1 in lipid metabolism. SREBP-1c and SREBP are two major transcription factors regulating the synthesis of triglyceride (TG) in hepatocytes. SREBP-1c and SREBP are key regulators of many lipogenic genes, including acc1 and FASN. It is reported that SIRT1 can reduce the transcriptional activity of SREBP-1c and its binding ability with the target gene by deacetylating the DNA binding domain of SREBP-1c, resulting in ubiquitination and proteasome degradation. The up-regulation of ChREBP expression in cirt1 knockout mice is related to the increase of histone H3K9 and histone H4K16 acetylation in the ChREBP promoter caused by the loss of SIRT1 deacetylase activity.
In addition to reducing fat production, SIRT1 also increases fatty acid oxidation by activating PPAR β / peroxisome proliferative activated receptor γ coactivator 1 α (PGC-1 α) signaling pathway. PGC-1 α is a transcription coactivator, which interacts with PPAR α and promotes PPAR - α gene transcription. Therefore, PPAR - α induces the expression of fatty acid catabolism gene. In conclusion, SIRT1 plays an important role in the regulation of liver lipid metabolism by regulating srebp1c / ChREBP dependent adipogenesis and PPAR α / PGC1 dependent α - dependent fatty acid β oxidation. In addition to SIRT1, SIRT3, which is mainly located in mitochondrial matrix, is also a regulatory factor of liver lipid metabolism. In the absence of SIRT3, mice fed a high-fat diet increased the acetylation of liver proteins and decreased the activity of respiratory complexes III and IV. In vitro, SIRT3 overexpression significantly reduced lipid accumulation in oleic acid induced HepG2 cells, suggesting that SIRT3 is another potential therapeutic target for fatty liver. SIRT6 has also been reported to promote lipid metabolism in the liver. SIRT6 deficiency resulted in up regulation of key genes involved in long-chain fatty acid uptake and down regulation of genes involved in fatty acid β oxidation. SIRT6 expression in human fatty liver patients was significantly reduced.
FOXO transcription factor has been identified as a key regulator of liver metabolism. In mammals, FOXO family consists of FoxO1, FoxO3, foxo4 and foxo6, which are widely expressed in vivo. FOXO transcription factor is the main target of insulin. In general, insulin promotes Akt mediated phosphorylation of FoxO proteins, stimulates their transfer from the nucleus to the cytoplasm, thereby inhibiting their role in gene expression. Recent studies have shown that FOXO protein stimulates the expression of ATGL, mediates the first step of lipolysis, and inhibits the interaction between G0 / G1 switch-2 protein (g0s2) and ATGL. In vivo, liver specific FoxO1 / 3 / 4 triple knockout mice (ltko) showed severe liver steatosis compared with WT control group when they were treated with high fat diet or moderate high fat and cholesterol diet. In addition, since autophagy-related 14 (atg14) has been proved to be a direct target of FoxOs, FoxOs can activate autophagy pathway to promote lipid decomposition. Compared with other FOXO subtypes, the amino acid sequence of foxo6 has the lowest homology (about 30%), indicating that its function is different from that of FoxO subfamily. Foxo6 promotes the production of lipid transfer proteins in the liver, such as microsomal triglyceride transfer protein (MTP). MTP can dimerize with its small subunit protein disulfide isomerase in endoplasmic reticulum, thus catalyzing the transport of lipids to new apolipoproteins B, which is the key process to mediate the secretion of very low density lipoprotein and chylomicrons.
FoxOs plays an important role in liver lipid homeostasis by inhibiting fat production, promoting the decomposition and output of triglycerides in hepatocytes. SREBP, SREBPs, are highly conserved in different species and regulate the expression of genes involved in lipid metabolism. There are three subtypes of SREBP, including SREBP-1a, SREBP-1c and SREBP-2. SREBP-1c is the main subtype expressed in the liver. It has been found that SREBP-1c preferentially controls the gene expression of fatty acid synthesis, while SREBP-2 regulates the transcription of cholesterol metabolism related genes. In endoplasmic reticulum, SREBPs are synthesized in the early form of membrane binding. Only through ER / Golgi process can they form active mature form through two protein hydrolysis processes. SREBPs are anchored on ER membrane by two transmembrane helices related to SREBP cleavage activator protein (SCAP) and endoplasmic reticulum retention protein (insig). The SREBP-Scap complex was then isolated from insig and migrated to Golgi via COPII coated vesicles. In Golgi apparatus, SREBPs are cleaved by site 1 (S1P) and site 2 (S2p) proteases, making the N-terminal cytoplasmic part of the protein enter the nucleus to perform its function. SREBP-1c mRNA levels are regulated by nutritional status in vivo. The expression of SREBP-1c mRNA in liver can be highly induced when high carbohydrate diet is given, but it can be inhibited when fasting. This process is regulated by hormones, including insulin, th and glucagon. The key role of mTORC1 in the regulation of SREBP-1c transcription has been identified. The protein level of mature SREBP-1c and the expression level of lipogenic gene were inhibited by rapamycin, an inhibitor of mTORC1. In addition, mTORC1 can phosphorylate the two main downstream targets of promoter 4E binding protein (4e BP) and p70 ribosomal S6 kinase (P70S6K). In turn, P70S6K promoted the protein hydrolysis of SREBP-1c protein. It has also been reported that clusterin is an 80 kDa disulfide linked heterodimer protein, which negatively regulates liver fat production by inhibiting the expression of SREBP-1c. More specifically, clusterin inhibits SREBP-1c expression by directly inhibiting srebp1c promoting activity and / or by inhibiting liver X receptor (LXR) and specific protein 1 activity.
Inflammatory cytokines
Inflammation plays an important role in the pathogenesis of various liver diseases, especially fatty liver. Cytokine is an important signal molecule, involved in the regulation of many physiological and pathological pathways. In this paper, we will discuss the two most studied proinflammatory cytokines IL-6 and TNF - α in liver metabolism, as shown in Table 1. IL-6 is a multifunctional cytokine, which has a wide range of biological activities in many organs. It can also act as a proinflammatory or anti-inflammatory medium. In the context of metabolic disorders. IL-6 has been identified as a key factor of hyperinsulinemia, insulin resistance and dyslipidemia. It was found that the concentration of IL-6 in adipose tissue of obese patients was higher than that of healthy group. In addition, IL-6 produced by adipose tissue can induce the secretion of VLDL in liver, thus affecting the lipid metabolism of liver. It was also reported that liver oxidative stress was positively correlated with the increase of serum IL-6 level and with the disorder of lipid homeostasis. On the contrary, IL-6 can protect liver from various forms of liver injury by regulating immune response. Mice lacking IL-6 tended to aggravate alcohol-induced lipid accumulation, which could be improved by injecting IL-6. Another report showed that IL-6 treatment reduced liver steatosis, accompanied by down-regulation of TNF - α, activation of PPAR - α, and promotion of fatty acid β oxidation. At the same time, the study of hepatoma cell lines in vitro showed that IL-6 reduced the mRNA level of SREBP-1c,