乙酸、非酯化脂肪酸、生长激素和催乳素调控奶牛肝细胞脂代谢的信号机制
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摘要
乳脂是牛奶的重要营养成分，乳脂的合成受到机体神经内分泌激素、细胞因子和营养代谢信号等的调节。肝脏是奶牛机体分配调节乳脂前体物的重要组织器官，奶牛泌乳期间，肝脏在神经内分泌激素、细胞因子和营养代谢信号的作用下，将乳腺外组织的营养物质优先流向乳腺，用于乳脂等营养物质的合成，发挥能量迁移作用。生长激素（Growth hormone，GH）和催乳素（Prolactin，PRL）是调节奶牛乳脂合成的重要激素；此外，近几年也研究发现乳脂前体物乙酸和非酯化脂肪酸（Non-esterified fatty acids，NEFAs）等营养代谢信号也可作为信号分子影响肝脏脂代谢基因的表达。所以明确GH、PRL、乙酸和NEFAs调节奶牛肝脏脂代谢的信号机制对人工干预提高乳脂有重要理论意义。所以本研究利用体外培养奶牛肝细胞，研究GH、PRL、乙酸和NEFAs调控奶牛肝细胞脂代谢的信号传导通路。
乙酸激活奶牛肝细胞腺苷酸活化蛋白激酶（AMP-activated protein kinase，AMPK）信号通路，调节肝细胞脂代谢。乙酸进入肝细胞后代谢成乙酰辅酶A，消耗肝细胞内ATP，使AMP/ATP比值增加，增加AMPKα的磷酸化，促进过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptor α，PPARα）的表达和转录活性，进而上调脂氧化关键酶基因的表达；激活的AMPKα抑制固醇调节元件结合蛋白（Sterol regulatory element-binding protein1c，SREBP-1c）和碳水化合物反应元件结合蛋白（Carbohydrate responsive element-bindingprotein，ChREBP）的表达和转录活性，下调脂合成关键酶基因的表达；同时激活的AMPKα抑制乙酰辅酶A羧化酶（Acetyl-CoA carboxylase1，ACC1）活性，促进肉碱酯酰转移酶1（Carnitine palmitoyltransferase1，CPT1）活性。表明乙酸激活奶牛肝细胞AMPK信号通路，促进脂氧化，降低脂合成，使肝细胞内甘油三酯（Triglyceride，TG）含量降低，减少肝脂蓄积。
NEFAs调控奶牛肝细胞脂代谢的AMPK信号机制。NEFAs通过上调肝脏激酶B1（Liver kinase B1，LKB1）的蛋白表达，增加AMPKα磷酸化水平，促进PPARα的表达和转录活性，另一方面NEFAs以配体激活物的形式独立于AMPKα直接激活PPARα，上调脂氧化基因表达。激活的AMPKα抑制SREBP-1c和ChREBP的表达和转录活性，下调脂合成基因的表达。同时激活的AMPKα抑制ACC1酶活性，增加CPT-1酶活性。NEFAs激活肝细胞AMPK信号通路，增加脂氧化作用，抑制脂合成作用。
GH激活肝细胞Janus激酶-信号转导子和转录激活子（Janus kinase2--transcription factor signal transducer and activator of transcription5，JAK2-STAT5）通路，STAT5磷酸化水平增加，促进肝细胞胰岛素样生长因子1（Insulin-like growth factor，IGF-1）的表达、合成和分泌。IGF-1以自分泌和旁分泌的形式激活磷脂酰肌醇3-激酶蛋白激酶B（Phosphatidyl inositol3-kinase-protein kinase B，PI3K-Akt）信号通路，促进SREBP-1c表达和转录活性，增强肝细胞的TG的合成和转运，为乳脂合成提供更多的乳脂前体物。此外GH激活JAK2-STAT5通路，STAT5磷酸化水平增加，抑制PPARα活性，降低肝细胞脂氧化作用。
PRL激活肝细胞PI3K-Akt信号通路，促进SREBP-1c表达和转录活性，上调肝细胞脂合成和转运基因的表达，促进肝细胞TG合成和输出，为乳脂合成提供更多的乳脂前体物。
根据以上结果显示，乳脂前体物乙酸和NEFAs促进肝细胞脂氧化，降低脂合成，减少肝脂蓄积；GH和PRL促进肝细胞脂合成和转运，为乳脂合成提供更多的乳脂前体物。
Milk fat is an important nutrient composition in milk. The synthesis of milk fat isregulated by neuroendocrine hormone, cytokines, and nutrition metabolic signals suchas milk fat precursors. Liver is the main organ for regulating and assigning milk fatprecursors. Liver transports the nutrition to breast for milk fat synthesis under theregulation of neuroendocrine hormone, cytokines, and nutrition metabolic signals indairy cows of lactation period. Growth hormone (GH) and prolactin (PRL) is the mostimportant hormone for the regulation of milk fat synthesis in dairy cows. Furthermore,several studies demonstrated that the acetic acid and non-esterified fatty acids(NEFAs) act as signaling molecules to regulate the expression of lipid metabolismgenes in the liver. Therefore, the objective of the present experiment was toinvestigate the signaling mechanism of GH, PRL, acetic acid and NEFAs on thehepatic lipid metabolism in the bovine hepatocytes cultured in vitro, which shouldprovide valuable information to improve the content of milk fat in dairy cows.
Acetic acid regulates the lipid metabolism through AMP-activated protein kinase(AMPK) signaling pathway. Acetic acid is metabolized to acetyl-CoA in hepatocytes withthe consumption of ATP. An elevated AMP/ATP ratio increases the phosphorylation andactivity of AMPKα. Activated AMPKα increases the expression and transcriptional activityof peroxisome proliferator-activated receptor α (PPARα), thereby increasing the expression oflipolytic genes. Furthermore, activated AMPKα inhibits the expression and transcriptionalactivity of sterol regulatory element-binding protein1c (SREBP-1c) and carbohydrateresponsive element-binding protein (ChREBP), thereby reducing the expression of lipogenicgenes. In addition, activated AMPKα directly phosphorylate acetyl-CoA carboxylase1(ACC1) and inhibit its activity, and indirectly increase carnitine palmitoyltransferase1(CPT-1) activity. Consequently, acetic acid activates AMPKα signaling pathway, whichincreases lipolysis and decreases lipid synthesis in bovine hepatocytes, thereby reducing hepatic fat accumulation in dairy cows.
NEFAs regulate the lipid metabolism through AMPK signaling pathway. NEFAsactivate AMPKα through increasing the expression of liver kinase B1. Activated AMPKαincreases the expression and transcriptional activity of PPARα. NEFAs also activate PPARαindependent of AMPKα in a ligand manner. Activated PPARα increases the expression oflipolytic genes. Activated AMPKα inhibits the expression and transcriptional activity ofSREBP-1c and ChREBP, thereby reducing the expression of the lipogenic genes. In addition,activated AMPKα directly phosphorylate ACC1and inhibit its activity, and indirectly increaseCPT1activity. Consequently, NEFAs increase lipid oxidization and inhibit lipid synthesis inbovine hepatocytes to produce more ATP.
GH activates Janus kinase2-transcription factor signal transducer and activatorof transcription5(JAK2-STAT5) signaling pathway to promote the synthesis andsecretion of insulin-like growth factor (IGF-1). IGF-1activates phosphatidyl inositol3-kinase-protein kinase B (PI3K-Akt) signaling pathway, which increases theexpression and transcriptional activity of SREBP-1c, thereby increasing lipid synthsisand transportion in bovine hepatocytes. The synthesized TG is used for the syntheis ofmilk fat. Furthermore, GH activates JAK2-STAT5signaling pathway, which inhibitsthe expression and transcriptional activity of PPARα, thereby decreasing lipidoxidation in bovine hepatocytes.
PRL activates PI3K-Akt signaling pathway, which increases the expression andtranscriptional activity of SREBP-1c. Activated SREBP-1c increases the expression of lipidsynthsis and transportion genes, which promotes the synthesis and transportion of TG inbovine hepatocytes, thereby providing more precursors for the milk fat synthsis.
In summary, acetic acid and NEFAs increase lipid oxidation and decrease lipidsynthesis in bovine hepatocytes, which reduces fat accumation. GH and PRL increaselipid synthsis and transportion in bovine hepatocytes, thereby providing more milk fatprecursors for milk fat synthesis.
乙酸激活奶牛肝细胞腺苷酸活化蛋白激酶（AMP-activated protein kinase，AMPK）信号通路，调节肝细胞脂代谢。乙酸进入肝细胞后代谢成乙酰辅酶A，消耗肝细胞内ATP，使AMP/ATP比值增加，增加AMPKα的磷酸化，促进过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptor α，PPARα）的表达和转录活性，进而上调脂氧化关键酶基因的表达；激活的AMPKα抑制固醇调节元件结合蛋白（Sterol regulatory element-binding protein1c，SREBP-1c）和碳水化合物反应元件结合蛋白（Carbohydrate responsive element-bindingprotein，ChREBP）的表达和转录活性，下调脂合成关键酶基因的表达；同时激活的AMPKα抑制乙酰辅酶A羧化酶（Acetyl-CoA carboxylase1，ACC1）活性，促进肉碱酯酰转移酶1（Carnitine palmitoyltransferase1，CPT1）活性。表明乙酸激活奶牛肝细胞AMPK信号通路，促进脂氧化，降低脂合成，使肝细胞内甘油三酯（Triglyceride，TG）含量降低，减少肝脂蓄积。
NEFAs调控奶牛肝细胞脂代谢的AMPK信号机制。NEFAs通过上调肝脏激酶B1（Liver kinase B1，LKB1）的蛋白表达，增加AMPKα磷酸化水平，促进PPARα的表达和转录活性，另一方面NEFAs以配体激活物的形式独立于AMPKα直接激活PPARα，上调脂氧化基因表达。激活的AMPKα抑制SREBP-1c和ChREBP的表达和转录活性，下调脂合成基因的表达。同时激活的AMPKα抑制ACC1酶活性，增加CPT-1酶活性。NEFAs激活肝细胞AMPK信号通路，增加脂氧化作用，抑制脂合成作用。
GH激活肝细胞Janus激酶-信号转导子和转录激活子（Janus kinase2--transcription factor signal transducer and activator of transcription5，JAK2-STAT5）通路，STAT5磷酸化水平增加，促进肝细胞胰岛素样生长因子1（Insulin-like growth factor，IGF-1）的表达、合成和分泌。IGF-1以自分泌和旁分泌的形式激活磷脂酰肌醇3-激酶蛋白激酶B（Phosphatidyl inositol3-kinase-protein kinase B，PI3K-Akt）信号通路，促进SREBP-1c表达和转录活性，增强肝细胞的TG的合成和转运，为乳脂合成提供更多的乳脂前体物。此外GH激活JAK2-STAT5通路，STAT5磷酸化水平增加，抑制PPARα活性，降低肝细胞脂氧化作用。
PRL激活肝细胞PI3K-Akt信号通路，促进SREBP-1c表达和转录活性，上调肝细胞脂合成和转运基因的表达，促进肝细胞TG合成和输出，为乳脂合成提供更多的乳脂前体物。
根据以上结果显示，乳脂前体物乙酸和NEFAs促进肝细胞脂氧化，降低脂合成，减少肝脂蓄积；GH和PRL促进肝细胞脂合成和转运，为乳脂合成提供更多的乳脂前体物。
Milk fat is an important nutrient composition in milk. The synthesis of milk fat isregulated by neuroendocrine hormone, cytokines, and nutrition metabolic signals suchas milk fat precursors. Liver is the main organ for regulating and assigning milk fatprecursors. Liver transports the nutrition to breast for milk fat synthesis under theregulation of neuroendocrine hormone, cytokines, and nutrition metabolic signals indairy cows of lactation period. Growth hormone (GH) and prolactin (PRL) is the mostimportant hormone for the regulation of milk fat synthesis in dairy cows. Furthermore,several studies demonstrated that the acetic acid and non-esterified fatty acids(NEFAs) act as signaling molecules to regulate the expression of lipid metabolismgenes in the liver. Therefore, the objective of the present experiment was toinvestigate the signaling mechanism of GH, PRL, acetic acid and NEFAs on thehepatic lipid metabolism in the bovine hepatocytes cultured in vitro, which shouldprovide valuable information to improve the content of milk fat in dairy cows.
Acetic acid regulates the lipid metabolism through AMP-activated protein kinase(AMPK) signaling pathway. Acetic acid is metabolized to acetyl-CoA in hepatocytes withthe consumption of ATP. An elevated AMP/ATP ratio increases the phosphorylation andactivity of AMPKα. Activated AMPKα increases the expression and transcriptional activityof peroxisome proliferator-activated receptor α (PPARα), thereby increasing the expression oflipolytic genes. Furthermore, activated AMPKα inhibits the expression and transcriptionalactivity of sterol regulatory element-binding protein1c (SREBP-1c) and carbohydrateresponsive element-binding protein (ChREBP), thereby reducing the expression of lipogenicgenes. In addition, activated AMPKα directly phosphorylate acetyl-CoA carboxylase1(ACC1) and inhibit its activity, and indirectly increase carnitine palmitoyltransferase1(CPT-1) activity. Consequently, acetic acid activates AMPKα signaling pathway, whichincreases lipolysis and decreases lipid synthesis in bovine hepatocytes, thereby reducing hepatic fat accumulation in dairy cows.
NEFAs regulate the lipid metabolism through AMPK signaling pathway. NEFAsactivate AMPKα through increasing the expression of liver kinase B1. Activated AMPKαincreases the expression and transcriptional activity of PPARα. NEFAs also activate PPARαindependent of AMPKα in a ligand manner. Activated PPARα increases the expression oflipolytic genes. Activated AMPKα inhibits the expression and transcriptional activity ofSREBP-1c and ChREBP, thereby reducing the expression of the lipogenic genes. In addition,activated AMPKα directly phosphorylate ACC1and inhibit its activity, and indirectly increaseCPT1activity. Consequently, NEFAs increase lipid oxidization and inhibit lipid synthesis inbovine hepatocytes to produce more ATP.
GH activates Janus kinase2-transcription factor signal transducer and activatorof transcription5(JAK2-STAT5) signaling pathway to promote the synthesis andsecretion of insulin-like growth factor (IGF-1). IGF-1activates phosphatidyl inositol3-kinase-protein kinase B (PI3K-Akt) signaling pathway, which increases theexpression and transcriptional activity of SREBP-1c, thereby increasing lipid synthsisand transportion in bovine hepatocytes. The synthesized TG is used for the syntheis ofmilk fat. Furthermore, GH activates JAK2-STAT5signaling pathway, which inhibitsthe expression and transcriptional activity of PPARα, thereby decreasing lipidoxidation in bovine hepatocytes.
PRL activates PI3K-Akt signaling pathway, which increases the expression andtranscriptional activity of SREBP-1c. Activated SREBP-1c increases the expression of lipidsynthsis and transportion genes, which promotes the synthesis and transportion of TG inbovine hepatocytes, thereby providing more precursors for the milk fat synthsis.
In summary, acetic acid and NEFAs increase lipid oxidation and decrease lipidsynthesis in bovine hepatocytes, which reduces fat accumation. GH and PRL increaselipid synthsis and transportion in bovine hepatocytes, thereby providing more milk fatprecursors for milk fat synthesis.
引文
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