The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeos...The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size,and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor(FXR)and the G-protein-coupled bile acid receptor(TGR5).展开更多
Helicobacter pylori(H.pylori)is still the most prevalent infection of the world.Colonization of the stomach by this agent will invariably induce chronic gastritis which is a low-grade inflammatory state leading to loc...Helicobacter pylori(H.pylori)is still the most prevalent infection of the world.Colonization of the stomach by this agent will invariably induce chronic gastritis which is a low-grade inflammatory state leading to local complications(peptic ulcer,gastric cancer,lymphoma)and remote manifestations.While H.pylori does not enter circulation,these extragastric manifestations are probably mediated by the cytokines and acute phase proteins produced by the inflammed mucosa.The epidemiologic link between the H.pylori infection and metabolic changes is inconstant and controversial.Growth delay was described mainly in low-income regions with high prevalence of the infection,where probably other nutritional and social factors contribute to it.The timely eradication of the infection will lead to a more healthy development of the young population,along with preventing peptic ulcers and gastric cancer An increase of total,low density lipoprotein and high density liporotein cholesterol levels in some infected people creates an atherogenic lipid profile which could promote atherosclerosis with its complications,myocardial infarction,stroke and peripheral vascular disease.Well designed and adequately powered long-term studies are required to see whether eradication of the infection will prevent these conditions.In case of glucose metabolism,the most consistent association was found between H.pylori and insulin resistance:again,proof that eradication prevents this common metabolic disturbance is expected.The results of eradication with standard regimens in diabetics are significantly worse than in non-diabetic patients,thus,more active regimens must be found to obtain better results.Successful eradication itself led to an increase of body mass index and cholesterol levels in some populations,while in others no such changes were encountered.Uncertainities of the metabolic consequences of H.pylori infection must be clarified in the future.展开更多
Nonalcoholic fatty liver disease (NAFLD) is a group of diseases with excess fat in liver in the absence of a poorly defined limit of alcohol consumption. Most common variety, a universal public health problem, is asso...Nonalcoholic fatty liver disease (NAFLD) is a group of diseases with excess fat in liver in the absence of a poorly defined limit of alcohol consumption. Most common variety, a universal public health problem, is associated with insulin resistance caused by a host of genetic and epigenetic defects modulated by life style and environmental factors. In fact the term NAFLD is loose to incorporate so many etiologies except alcoholism and few other etiologies, presenting as fat in liver. However as a sign fatty liver is very important in predicting the risk of diabetes, cardiovascular disease, stroke, cirrhosis and cancer. Abnormal fat accumulation can result from several defects in nuclear receptors associated with lipid sensing, synthesis and oxidation like LXR, FXR, SREBP, ChREBP and PPAR; defects in the lipid influx-efflux channels, insulin signaling, proteins involved in fatty acid catabolism, defects in adipose tissue development and function, inappropriate nutrition and finally defects in neural regulatory mechanisms. The progress of the disease is determined by the basic defects which results in fat accumulation, an individual’s immunological response to the accumulated fat and its derivatives and the oxidant stress response. Congregation of unrelated genetic defects under same diagnosis ‘NAFLD’ can result in inefficient patient management. Further studies are required to understand the molecular basis of fatty liver to enable a personalized management of diseases presenting as fatty liver in the absence of alcohol abuse.展开更多
The liver plays a major role in the regulation , glucose, lipid and energy metabolism. Increasd hepatic fat deposit is a very common feature in obese, insulin-resistant patients, in metabolic syndrome, alcoholic steat...The liver plays a major role in the regulation , glucose, lipid and energy metabolism. Increasd hepatic fat deposit is a very common feature in obese, insulin-resistant patients, in metabolic syndrome, alcoholic steatohepatitis （ASH） and nonalchoholic fatty liver disaseas （NAFLD）. As a central organ for whole body lipid metabolism, disruption of the normal mechanisms for synthesis, transport and removal/ metabolism of long-chain fatty acids and triglycerides are the basis for the development of fatty liver. The exact mechanisms that link hepatic lipid accumulation, impaired glucose metabolism, and insulin resistance are unknown, but increasing evidence suggest that nuclear transcription factors play important roles. Members of the nuclear receptor superfamily, especially the peroxisome proliferator-activated receptors （PPARs） and the liver X receptor （LXR）, other factors such as sterol regulatory element binding proteins （SREBPs）, carbohydrate- response element-binding protein （ChREBP）, and nuclear transcription fator-κB （NF-κB） have emerged as dominant regulators of these processes, but the relative role of each of these factors in fatty liver disease is still undefined.展开更多
Mitofusin-2 （Mfn2） gene expression is positively correlated with insulin sensitivity in patients with type 2 diabetes. However, it is unclear if Mfn2 is involved in carbohydrate metabolism and lipid homeostasis. In ...Mitofusin-2 （Mfn2） gene expression is positively correlated with insulin sensitivity in patients with type 2 diabetes. However, it is unclear if Mfn2 is involved in carbohydrate metabolism and lipid homeostasis. In order to investigate the specific functions of Mfn2 in glycometabolism and lipid homeostasis in BALB/c mice, a RNA interference technique-mediated hydrodynamic injection was developed, in which short hairpin RNAs （shRNAs） were used to inhibit the Mfn2 expression in vivo. Seventy-two mice were randomly divided into two groups： the Mfn2 reduction group （Mfn2/shRNA） and the negative control group （NC）. Intraperitoneal glucose tolerance tests and intraperitoneal insulin tolerance tests were used to evaluate glycometabolism and insulin sensitivity. D-（3-3H） glucose or 3H2O was injected into the tail vein or intraperitoneally to facilitate the calculation of the rate of hepatic glucose production and fatty acid synthesis in vivo. The results showed that, in Mfn2/shRNA mice, the liver Mfn2 protein was significantly decreased, and fasting blood glucose concentrations were increased by approximately 48%, when compared with the NC mice. In parallel with the changes in fasting glucose levels, hepatic glucose production was significantly elevated in Mfn2/shRNA mice. When insulin was administrated, these mice exhibited impaired insulin tolerance. It was also found that the reduction of Mfn2 markedly decreased the rate of fatty acid synthesis in the liver, and the Mfn2/shRNA mice exhibited hypertriglyceridema. Taken together, our results indicate that Mfn2 plays an important role in maintaining glucose and lipid homeostasis, and in the development of insulin resistance in vivo.展开更多
Cancer cells uniquely reprogram their cellular activities to support their rapid proliferation and migration and to coun-teract metabolic and genotoxic stress during cancer progression.In this reprograming,cancer cell...Cancer cells uniquely reprogram their cellular activities to support their rapid proliferation and migration and to coun-teract metabolic and genotoxic stress during cancer progression.In this reprograming,cancer cells’metabolism and other cellular activities are integrated and mutually regulated,and cancer cells modulate metabolic enzymes spatially and temporally so that these enzymes not only have altered metabolic activities but also have modulated subcellular localization and gain non-canonical functions.This review and several others in this issue of Cancer Communications discuss these enzymes’newly acquired functions and the non-canonical functions of some metabolites as features of cancer cell metabolism,which play critical roles in various cellular activities,including gene expression,anabolism,catabolism,redox homeostasis,and DNA repair.展开更多
Stearyl coenzyme A desaturase(SCD), also known as delta-9 desaturase, catalyzes the rate-limiting step in the formation of monounsaturated fatty acids.In mammals, depletion or inhibition of SCD activity generally lead...Stearyl coenzyme A desaturase(SCD), also known as delta-9 desaturase, catalyzes the rate-limiting step in the formation of monounsaturated fatty acids.In mammals, depletion or inhibition of SCD activity generally leads to a decrease in triglycerides and cholesteryl esters. However, the endogenous role of scd in teleost fish remains unknown. Here, we generated a zebrafish scd mutant(scd-/-) to elucidate the role of scd in lipid metabolism and sexual development. Gas chromatography-mass spectrometry(GC-MS) showed that the scd-/- mutants had increased levels of saturated fatty acids C16:0 and C18:0, and decreased levels of monounsaturated fatty acids C16:1 and C18:1. The mutant fish displayed a short stature and an enlarged abdomen during development. Unlike Scd-/ -mammals, the scd-/- zebrafish showed significantly increased fat accumulation in the whole body,especially in the liver, leading to hepatic mitochondrial dysfunction and severe cell apoptosis.Mechanistically, srebf1, a gene encoding a transcriptional activator related to adipogenesis,acc1 and acaca, genes involved in fatty acid synthesis, and dgat2, a key gene involved in triglyceride synthesis, were significantly upregulated in mutant livers to activate fatty acid biosynthesis and adipogenesis. The scd-/- males exhibited defective natural mating behavior due to defective genital papillae but possessed functional mature sperm. All defects in the scd-/- mutants could be rescued by ubiquitous transgenic overexpression of scd. In conclusion, our study demonstrates that scd is indispensable for maintaining lipid homeostasis and development of secondary sexual characteristics in zebrafish.展开更多
Brown adipose tissue (BAT) plays an essential role in non-shivering thermogenesis. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) is identified as a lipid transporter that reciprocally transfers ph...Brown adipose tissue (BAT) plays an essential role in non-shivering thermogenesis. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) is identified as a lipid transporter that reciprocally transfers phospholipids between intracellular membrane structures. However, the physiological significance of PITPNC1 and its regulatory mechanism remain unclear. Here, we demonstrate that PITPNC1 is a key player in thermogenesis of BAT. While Pitpnc1^(−/−) mice do not differ with wildtype mice in body weight and insulin sensitivity on either chow or high-fat diet, they develop hypothermia when subjected to acute cold exposure at 4℃. The Pitpnc1^(−/−) brown adipocytes exhibit defective β-oxidation and abnormal thermogenesis-related metabolism pathways in mitochondria. The deficiency of lipid mobilization in Pitpnc1^(−/−) brown adipocytes might be the result of excessive accumulation of phosphatidylcholine and a reduction of phosphatidic acid. Our findings have uncovered significant roles of PITPNC1 in mitochondrial phospholipid homeostasis and BAT thermogenesis.展开更多
基金supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH,No.R01DK047987)supported by a Research Supplement to Promote Diversity in Health Related Research from the NIH
文摘The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size,and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor(FXR)and the G-protein-coupled bile acid receptor(TGR5).
文摘Helicobacter pylori(H.pylori)is still the most prevalent infection of the world.Colonization of the stomach by this agent will invariably induce chronic gastritis which is a low-grade inflammatory state leading to local complications(peptic ulcer,gastric cancer,lymphoma)and remote manifestations.While H.pylori does not enter circulation,these extragastric manifestations are probably mediated by the cytokines and acute phase proteins produced by the inflammed mucosa.The epidemiologic link between the H.pylori infection and metabolic changes is inconstant and controversial.Growth delay was described mainly in low-income regions with high prevalence of the infection,where probably other nutritional and social factors contribute to it.The timely eradication of the infection will lead to a more healthy development of the young population,along with preventing peptic ulcers and gastric cancer An increase of total,low density lipoprotein and high density liporotein cholesterol levels in some infected people creates an atherogenic lipid profile which could promote atherosclerosis with its complications,myocardial infarction,stroke and peripheral vascular disease.Well designed and adequately powered long-term studies are required to see whether eradication of the infection will prevent these conditions.In case of glucose metabolism,the most consistent association was found between H.pylori and insulin resistance:again,proof that eradication prevents this common metabolic disturbance is expected.The results of eradication with standard regimens in diabetics are significantly worse than in non-diabetic patients,thus,more active regimens must be found to obtain better results.Successful eradication itself led to an increase of body mass index and cholesterol levels in some populations,while in others no such changes were encountered.Uncertainities of the metabolic consequences of H.pylori infection must be clarified in the future.
文摘Nonalcoholic fatty liver disease (NAFLD) is a group of diseases with excess fat in liver in the absence of a poorly defined limit of alcohol consumption. Most common variety, a universal public health problem, is associated with insulin resistance caused by a host of genetic and epigenetic defects modulated by life style and environmental factors. In fact the term NAFLD is loose to incorporate so many etiologies except alcoholism and few other etiologies, presenting as fat in liver. However as a sign fatty liver is very important in predicting the risk of diabetes, cardiovascular disease, stroke, cirrhosis and cancer. Abnormal fat accumulation can result from several defects in nuclear receptors associated with lipid sensing, synthesis and oxidation like LXR, FXR, SREBP, ChREBP and PPAR; defects in the lipid influx-efflux channels, insulin signaling, proteins involved in fatty acid catabolism, defects in adipose tissue development and function, inappropriate nutrition and finally defects in neural regulatory mechanisms. The progress of the disease is determined by the basic defects which results in fat accumulation, an individual’s immunological response to the accumulated fat and its derivatives and the oxidant stress response. Congregation of unrelated genetic defects under same diagnosis ‘NAFLD’ can result in inefficient patient management. Further studies are required to understand the molecular basis of fatty liver to enable a personalized management of diseases presenting as fatty liver in the absence of alcohol abuse.
基金This study was supported by the grants from the National Natural Science Foundation of China(Key Program,No.30530360)the National Basic Research Program of China(No.2006CB503907)
文摘The liver plays a major role in the regulation , glucose, lipid and energy metabolism. Increasd hepatic fat deposit is a very common feature in obese, insulin-resistant patients, in metabolic syndrome, alcoholic steatohepatitis （ASH） and nonalchoholic fatty liver disaseas （NAFLD）. As a central organ for whole body lipid metabolism, disruption of the normal mechanisms for synthesis, transport and removal/ metabolism of long-chain fatty acids and triglycerides are the basis for the development of fatty liver. The exact mechanisms that link hepatic lipid accumulation, impaired glucose metabolism, and insulin resistance are unknown, but increasing evidence suggest that nuclear transcription factors play important roles. Members of the nuclear receptor superfamily, especially the peroxisome proliferator-activated receptors （PPARs） and the liver X receptor （LXR）, other factors such as sterol regulatory element binding proteins （SREBPs）, carbohydrate- response element-binding protein （ChREBP）, and nuclear transcription fator-κB （NF-κB） have emerged as dominant regulators of these processes, but the relative role of each of these factors in fatty liver disease is still undefined.
文摘Mitofusin-2 （Mfn2） gene expression is positively correlated with insulin sensitivity in patients with type 2 diabetes. However, it is unclear if Mfn2 is involved in carbohydrate metabolism and lipid homeostasis. In order to investigate the specific functions of Mfn2 in glycometabolism and lipid homeostasis in BALB/c mice, a RNA interference technique-mediated hydrodynamic injection was developed, in which short hairpin RNAs （shRNAs） were used to inhibit the Mfn2 expression in vivo. Seventy-two mice were randomly divided into two groups： the Mfn2 reduction group （Mfn2/shRNA） and the negative control group （NC）. Intraperitoneal glucose tolerance tests and intraperitoneal insulin tolerance tests were used to evaluate glycometabolism and insulin sensitivity. D-（3-3H） glucose or 3H2O was injected into the tail vein or intraperitoneally to facilitate the calculation of the rate of hepatic glucose production and fatty acid synthesis in vivo. The results showed that, in Mfn2/shRNA mice, the liver Mfn2 protein was significantly decreased, and fasting blood glucose concentrations were increased by approximately 48%, when compared with the NC mice. In parallel with the changes in fasting glucose levels, hepatic glucose production was significantly elevated in Mfn2/shRNA mice. When insulin was administrated, these mice exhibited impaired insulin tolerance. It was also found that the reduction of Mfn2 markedly decreased the rate of fatty acid synthesis in the liver, and the Mfn2/shRNA mice exhibited hypertriglyceridema. Taken together, our results indicate that Mfn2 plays an important role in maintaining glucose and lipid homeostasis, and in the development of insulin resistance in vivo.
基金supported by the National Institute of Neurological Disorders and Stroke grant R01 NS089754(to Z.L.)by the National Cancer Institute(NCI)grant 1R01 CA204996(to Z.L.)+1 种基金by the National Institutes of Health/NCI through MD Anderson’s Cancer Center Support grant P30CA016672Brain Cancer Specialized Program of Research Excellence grant 2P50 CA127001。
文摘Cancer cells uniquely reprogram their cellular activities to support their rapid proliferation and migration and to coun-teract metabolic and genotoxic stress during cancer progression.In this reprograming,cancer cells’metabolism and other cellular activities are integrated and mutually regulated,and cancer cells modulate metabolic enzymes spatially and temporally so that these enzymes not only have altered metabolic activities but also have modulated subcellular localization and gain non-canonical functions.This review and several others in this issue of Cancer Communications discuss these enzymes’newly acquired functions and the non-canonical functions of some metabolites as features of cancer cell metabolism,which play critical roles in various cellular activities,including gene expression,anabolism,catabolism,redox homeostasis,and DNA repair.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA24010108)National Natural Science Foundation of China(31872554,32172952)Project from the State Key Laboratory of Freshwater Ecology and Biotechnology(2019FBZ05)。
文摘Stearyl coenzyme A desaturase(SCD), also known as delta-9 desaturase, catalyzes the rate-limiting step in the formation of monounsaturated fatty acids.In mammals, depletion or inhibition of SCD activity generally leads to a decrease in triglycerides and cholesteryl esters. However, the endogenous role of scd in teleost fish remains unknown. Here, we generated a zebrafish scd mutant(scd-/-) to elucidate the role of scd in lipid metabolism and sexual development. Gas chromatography-mass spectrometry(GC-MS) showed that the scd-/- mutants had increased levels of saturated fatty acids C16:0 and C18:0, and decreased levels of monounsaturated fatty acids C16:1 and C18:1. The mutant fish displayed a short stature and an enlarged abdomen during development. Unlike Scd-/ -mammals, the scd-/- zebrafish showed significantly increased fat accumulation in the whole body,especially in the liver, leading to hepatic mitochondrial dysfunction and severe cell apoptosis.Mechanistically, srebf1, a gene encoding a transcriptional activator related to adipogenesis,acc1 and acaca, genes involved in fatty acid synthesis, and dgat2, a key gene involved in triglyceride synthesis, were significantly upregulated in mutant livers to activate fatty acid biosynthesis and adipogenesis. The scd-/- males exhibited defective natural mating behavior due to defective genital papillae but possessed functional mature sperm. All defects in the scd-/- mutants could be rescued by ubiquitous transgenic overexpression of scd. In conclusion, our study demonstrates that scd is indispensable for maintaining lipid homeostasis and development of secondary sexual characteristics in zebrafish.
基金the National Key R&D Program of China(2018YFA0506900)the National Key R&D Program of China(2018YFA0800301)+3 种基金the National Natural Science Foundation of China(91857103)Shanghai Basic Research Field Project“Science and Technology Innovation Action Plan”(21JC1400400)the Lingang Laboratory(LG-QS-202204-06)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)。
文摘Brown adipose tissue (BAT) plays an essential role in non-shivering thermogenesis. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) is identified as a lipid transporter that reciprocally transfers phospholipids between intracellular membrane structures. However, the physiological significance of PITPNC1 and its regulatory mechanism remain unclear. Here, we demonstrate that PITPNC1 is a key player in thermogenesis of BAT. While Pitpnc1^(−/−) mice do not differ with wildtype mice in body weight and insulin sensitivity on either chow or high-fat diet, they develop hypothermia when subjected to acute cold exposure at 4℃. The Pitpnc1^(−/−) brown adipocytes exhibit defective β-oxidation and abnormal thermogenesis-related metabolism pathways in mitochondria. The deficiency of lipid mobilization in Pitpnc1^(−/−) brown adipocytes might be the result of excessive accumulation of phosphatidylcholine and a reduction of phosphatidic acid. Our findings have uncovered significant roles of PITPNC1 in mitochondrial phospholipid homeostasis and BAT thermogenesis.
