Figure 1. Lipid metabolism signaling pathway
Overview of lipid metabolism
Lipid is a general term for fats and lipids. It is an ester formed by the action of fatty acids and alcohols and its derivatives, collectively known as lipids. It is a major component of animals and plants and is also widely found in nature. Despite their much different chemical composition, structural physicochemical properties and biological functions, lipids all have a common feature, which can be extracted from cells and tissues with non-polar organic solutions. Fat metabolism is one of the three major material metabolisms, and its signal transduction pathway has a complex and fine regulatory network, which is mainly involved in the energy supply and storage of the organism, the composition of biofilm and other important life processes. Lipid metabolism mainly includes triglyceride (TG) metabolism, metabolism of cholesterol and its esters, and phospholipid and glycolipid metabolism. The stability of lipid metabolism is particularly important for the steady state maintenance of the body.
Lipid metabolism family
Lipid metabolism mainly includes triglyceride (TG) metabolism, metabolism of cholesterol and its esters, and phospholipid and glycolipid metabolism. In these metabolic processes, many proteases, receptors, transcription factors, etc. are involved, and they are regulated by some signal transduction pathways, forming a complex and fine regulatory network to maintain the lipid metabolism balance of cells and the whole body. Lipid metabolism transduction signal pathways mainly include peroxisome proliferator-activated receptor (PPARs) signal transduction pathway, liver X receptor (LXRs) signal transduction pathway, sterol regulatory element binding protein (SREBPs) signal transduction guide route and so on. The lipid metabolism signal transduction pathways are complex, and there are many downstream target genes regulated by each pathway, and each pathway is also regulated by each other. Many of these problems remain to be elucidated.
Lipid metabolism signaling pathway
Lipid metabolism signaling pathway cascade
Lipid metabolism can be explained from catabolism and anabolism. In lipid catabolism reaction, triglyceride turns into glycerol fatty acid under the action of lipase; fatty acid, ATP, fatty acyl-CoA turns into fatty acyl-CoA, AMP, PPi under synthetase. Among them, lipase is hormone-sensitive triglyceride lipase, which is the rate-limiting enzyme for lipolysis. When the sympathetic nerve is excited, the secretion of adrenaline and norepinephrine increases, the receptor acting on the surface of the adipocyte membrane activates adenylate cyclase, promotes the synthesis of cyclized adenosine monophosphate, activates a protein kinase that is dependent on cyclic adenosine monophosphate, and phosphorylates triglyceride lipase in cytosol. Fatty acid production rate increases. Fatty acid CoA formed after fatty acid activation depends on the mitochondrial membrane on the mitochondrial transport mechanism into the mitochondrial inner membrane. Carnitine is the most effective transport factor for fat transport to mitochondrial oxidative energy supply. Appropriate supplementation of L-carnitine can increase the utilization of fatty acids. Fatty acid CoA enters the mitochondrial matrix and dehydrogenates from the beta carbon atom. Chemical dehydrogenation, thiolysis, a new generation of 2 carbon atoms of fatty acyl-CoA and 1 molecule of acetyl-CoA, is called β-oxidation of saturated fatty acids, and unsaturated fatty acids are also β-oxidized. Mammals fatty acids in the body also have α-oxidation and ω-oxidation, and the product succinic acid enters the Krebs cycle to form CO2, H2O and a large amount of ATP. The 1 molecule of sugar is completely decomposed to form 36 molecules of ATP, and 1 molecule of soft fatty acid is completely decomposed to form 129 molecules ATP. Glycerol is converted into 3 molecules of glycerol phosphate by the action of glycerol phosphokinase, partially involved in the synthesis of triglycerides and phospholipids, partially into the glycolysis pathwayand part of the gluconeogenesis. Glycerol in a few tissues such as kidney and liver oxidation to CO2 and H2O, oxidation of one molecule of glycerol can produce 22 molecules of ATP. When glycerin is used for long-term endurance exercise, the utilization rate is increased, and it becomes an important substrate for gluconeogenesis. As an important source of blood sugar, it ensures relatively stable blood sugar in exercise. Excess carbohydrates in food are converted to triglycerides (TAG) in the liver, and very low-density lipoproteins (VLDLs). The process by which glucose is converted to fatty acids is called the de novo synthesis pathway (DNL) of fat, tightly regulated by hormones and nutritional status. In starvation, de novo synthesis of fat remains low level due to elevated blood glucagon and activation of the intracellular cyclic adenosine monophosphate (cAMP) pathway. After eating, elevated blood glucose and insulin levels stimulate the insulin signaling pathway, leading to protein kinases such as phosphatidylinositol 3-kinase (PI3K), AKT, atypical protein kinase C (aPKC), and mammalian rapamycin target protein complexes. Activation of lipids by mTORCs and protein phosphatases such as protein phosphatase 1 (pp1) and protein phosphatase 2 (pp2). A variety of proteases are involved in the regulation of fatty acid and triglyceride synthesis processes. These enzymes have very low activity when starved and are highly active after eating, thereby maintaining the balance of lipid metabolism in the body.
Carnitine: The role of carnitine in fat metabolism has been confirmed, that is, triacylglycerol decomposes long-chain fatty acids of more than ten carbons. Oxidative energy supply must first be activated in the myocyte cytoplasm with coenzyme A (CoA) in the presence of ATP to form fatty acyl groups. CoA must be transferred to the mitochondria to oxidatively decompose, but the fatty acyl-CoA cannot pass through the mitochondrial inner membrane, and the carnitine can be used as a long-chain fatty acid carrier to oxidize and supply energy through the mitochondrial inner membrane, which acts as a 3-hydroxyl acceptor of carnitine. The acyl group of fatty acyl-CoA is transferred into the mitochondrial inner membrane, which is then catalyzed by carnitine lipid acyltransferase II to separate the carnitine from the fatty acyl-CoA, and then reform the fatty acyl-CoA, which is continuously in the mitochondrial interstitial. β-oxidation, the resulting acetyl-CoA is decomposed into H2O and CO2 by the Krebs cycle, and at the same time releases a large amount of energy. The oxidation sites of lipids and acids are on the mitochondria, and the fatty acyl-CoA cannot enter the mitochondria, but the carnitine can carry the acyl group into the mitochondria to complete the fatty acid metabolism, so if the carnitine concentration is elevated, it can promote fatty acyl transport, thereby promoting fatty acid and fat metabolism. Zemel et al., after conducting a number of studies, proposed a preliminary mechanism for calcium regulation of fat metabolism, that is, a low-calcium diet leads to an increase in 1,25(OH)2-D3 levels and an increase in adipocyte Ca2+ influx, thereby stimulating insulin release and promoting fat production, inhibition of fat breakdown, decreased body heat production, eventually leading to fat accumulation and weight gain, while the effect of high calcium diet is exactly the opposite. As a calmodulin, 1,25(OH)2-D3 stimulates adipocyte Ca2+ influx to promote the activation of lipase synthase (FAS) and inhibit lipolysis, and to some extent, the dose-effect relationship is increased subsequently. Baran et al. found a high level with 1,25(OH)2-D3 in obesity studies. An affinity membrane-bound protein, when specifically bound to 1,25(OH)2-D3, mediates the regulation of intracellular Ca2+ concentration, which in turn affects lipid synthesis and decomposition. In the low-calcium diet, the level of 1,25(OH)2-D3 in the body is automatically increased. By binding to the membrane vitamin D receptor (mVDR), it stimulates a large amount of Ca2+ influx, eventually leading to an increase in triglycerides in the fat cells, the effect of dietary calcium on energy metabolism is related to the change of metabolic rate. It has been proved that the temperature of the body center of rats fed with high calcium diet and the expression of uncoupling protein UCP-2 is enhanced, and the energy utilization efficiency is decreased. UCP-2 is widely present in white adipose tissue. The main function is to control the production of heat, regulate insulin secretion and fatty acid utilization. It is observed that there is a direct dose-effect negative correlation between 1,25(OH)2-D3 and UCP-2 expression, and this effect is not dependent. In addition, UCP-2 regulates the function of insulin secretion by 1,25(OH)2. The regulation of D3 remains to be further studied. Once it is confirmed, it will provide a powerful theoretical supplement for the initial mechanism of calcium regulation of fat metabolism. Ca2+ is not only a key link in the regulation of energy metabolism by 1,25(OH)2-D3. At the same time, it is also an important link in the regulation of fat metabolism by other factors. And agouti is an obese gene expressed in human fat cells, and its target product of the carboxy terminus of Agouti protein is calcium ion channel in human body. These phenomena can be mimicked by activating receptor-dependent and voltage-dependent calcium channels and can be reversed by inhibiting Ca2+ channels. Experiments have shown that Agouti-induced obese rats are treated with calcium channel antagonists for 4 weeks. Obesity has been significantly improved. The high expression of Agouti protein in obesity patients induces the increase of calcium influx in fat cells, which is also one of the causes of energy metabolism disorder. So how does the influx of calcium ions play its role? Draznin et al found that Ca2+ in the adipocytes of obese patients was significantly higher than normal, and some people used Ca2+ influx inducer to induce intracellular Ca2+ concentration, which increased the basal level and insulin-stimulated lipid synthesis, and this effect can be reversed by calcium channel inhibitors. At the same time, intracellular Ca2+ inhibits lipolysis by activating phosphodiesterase (PDE), causing a decrease in cAMP and phosphorylation of hormone-sensitive lipase (HSL), Malonyl CoA. As the intermediate product of fatty acid synthesis, malonyl monoamide CoA is formed by carboxylation of acetyl CoA, ATP and HCO under the action of acetyl CoA carboxylase (ACC), which plays an important role in the synthesis of long-chain fatty acids. Studies have shown that the biological function of malonyl CoA is mainly manifested in two aspects. First, in the complex process of fat synthesis, malonyl CoA is used as a two-carbon unit donor to facilitate the synthesis of lipase. In the process of fatty acid oxidation and ketogenesis, malonyl CoA acts as an inhibitor, mainly inhibiting the fatty acylcarnitine transferase CPT1, when the body is rich in carbohydrate or high energy load. The conversion of glucose to fatty acids leads to an increase in malonyl CoA and promotes fatty acid synthesis. When hunger, prolonged endurance exercise or disease, the concentration of malonyl CoA decreases, which is beneficial to the oxidation of fatty acids. The sensitivity of malonyl CoA to inhibit fatty acid oxidation and CPT1 activity depends on the nutritional status of the body; when the glucose supply is abundant and converted into fatty acids, Acid monoacyl-CoA is at a high level and acts as a signal to inhibit fatty acid oxidation; when glucose is underutilized, or blood glucagon/insulin ratio increases (eg diabetes, fasting or prolonged exercise, etc.), liver malonyl CoA will decrease.
Relationship with disease
The nature of obesity is a disorder of lipid metabolism, and the rate of lipid consumption is lower than that of lipids. Therefore, the role of the lipid metabolism signaling pathway in obesity has been the research focus. Now studies have shown that the following proteins of lipid metabolism are involved in the formation of obesity: PPAGR found high expression in fat cells can increase the expression of fatty acid transporters and fatty acid transporters, stimulate the uptake and metabolism of fatty acids, so the high expression of PPARG in fat cells can make glycerol in fat cells and causing obesity. INSIG2 is a membrane protein on the endoplasmic reticulum that prevents SREBP from entering the Golgi apparatus and affects lipid synthesis. PLIN is a phospholipid protein that prevents lipase from encountering triacylglycerol in lipid droplets, thereby inhibiting the degradation of fat. Therefore, the role of lipid metabolism signaling pathway in the occurrence of obesity cannot be ignored.
Numerous studies have shown that lipid metabolism plays an important role in the pathogenesis of AD. The genome-wide correlation study (GWAS) by Harold and Lambert revealed AD-related genes and proteins, including known to increase the incidence of late-onset AD. The specific mechanism of susceptible apoe, and Clusterin (CLU), Complement receptor 1 (CR1), Phosphatidylinositol-binding clathrin assembly protein (PICALM) and Bridging integrin 1 needs further research.
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