Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease(NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors(PPARs) are transcr...Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease(NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors(PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation(mitochondrial and peroxisomal)and microsomal omega-oxidation, being markedly decreased by high-fat(HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.展开更多
Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the tr...Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols(i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids(i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates(i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.展开更多
Alteration of lipid metabolism has been increasingly recognized as a hallmark of cancer cells. The changes of expression and activity of lipid metabolizing enzymes are directly regulated by the activity of oncogenic s...Alteration of lipid metabolism has been increasingly recognized as a hallmark of cancer cells. The changes of expression and activity of lipid metabolizing enzymes are directly regulated by the activity of oncogenic signals. The dependence of tumor cells on the dysregulated lipid metabolism suggests that proteins involved in this process are excellent chemotherapeutic targets for cancer treatment. There are currently several drugs under development or in clinical trials that are based on specifically targeting the altered lipid metabolic pathways in cancer cells. Further understanding of dysregulated lipid metabolism and its associated signaling pathways will help us to better design efficient cancer therapeutic strategy.展开更多
Hatchery-roared juvenile black sea breams are characterized by a low level of highly unsaturated fatty acids in their bodies, as compared with wild fish. To assess the effect of docosahaxaenoic acid （DHA） on lipegen...Hatchery-roared juvenile black sea breams are characterized by a low level of highly unsaturated fatty acids in their bodies, as compared with wild fish. To assess the effect of docosahaxaenoic acid （DHA） on lipegenic and lipelysis enzymes, one-year fish were roared on a casein-based purified diet and a DHA fortified diet （ 1.5% DHA ethyl ester/kg diet） for 60 d, followed with a period of 55 d for starvation. Dietary DHA was effectively incorporated into the fish body. Fortification of DHA depressed activities of glucose-6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase as lipogenic enzymes in the hepatopancroas and intraperitoneal fat body. Carnitine palmitoyltransferase as lipolysis enzyme in the hepatopancreas was active in the DHA fortified fish. Starvation after feeding experiment induced increased carnitine palmitoyltransferase activity in both control and DHA fortified fish and the activity remained higher in the DHA fortified fish, while the monoenes were selectively consumed prior to highly unsaturated fatty acids. These results indicated that dietary DHA depressed lipogenesis and activated lipolysis.展开更多
AIM To investigate protective effects and molecular mechanisms of green tea polyphenols(GTP) on nonalcoholic fatty liver disease(NAFLD) in Zucker fatty(ZF) rats.METHODS Male ZF rats were fed a high-fat diet(HFD) for 2...AIM To investigate protective effects and molecular mechanisms of green tea polyphenols(GTP) on nonalcoholic fatty liver disease(NAFLD) in Zucker fatty(ZF) rats.METHODS Male ZF rats were fed a high-fat diet(HFD) for 2 wk then treated with GTP(200 mg/kg) or saline(5 m L/kg) for 8 wk, with Zucker lean rat as their control. At the end of experiment, serum and liver tissue were collected for measurement of metabolic parameters, alanine aminotransferase(ALT) and aspartate aminotransferase(AST), inflammatory cytokines and hepatic triglyceride and liver histology. Immunoblotting was used to detect phosphorylation of AMP-activated protein kinase(AMPK) acetyl-Co A carboxylase(ACC), and sterol regulatory element-binding protein 1c(SREBP1c). RESULTS Genetically obese ZF rats on a HFD presented with metabolic features of hepatic pathological changes comparable to human with NAFLD. GTP intervention decreased weight gain(10.1%, P = 0.052) and significantly lowered visceral fat(31.0%, P < 0.01). Compared with ZF-controls, GTP treatment significantly reduced fasting serum insulin, glucose and lipids levels. Reduction in serum ALT and AST levels(both P < 0.01) were observed in GTP-treated ZF rats. GTP treatment also attenuated the elevated TNFα and IL-6 in the circulation. The increased hepatic TG accumulation and cytoplasmic lipid droplet were attenuated by GTP treatment, associated with significantly increased expression of AMPK-Thr172(P < 0.05) and phosphorylated ACC and SREBP1c(both P < 0.05), indicating diminished hepatic lipogenesis and triglycerides out flux from liver in GTP treated rats. CONCLUSION The protective effects of GTP against HFD-induced NAFLD in genetically obese ZF rats are positively correlated to reduction in hepatic lipogenesis through upregulating the AMPK pathway.展开更多
The mechanistic target of rapamycin （mTOR） signaling pathway regulates many metabolic and physiological processes in different organs or tissues. DysregulaUon of mTOR signaling has been implicated in many human dise...The mechanistic target of rapamycin （mTOR） signaling pathway regulates many metabolic and physiological processes in different organs or tissues. DysregulaUon of mTOR signaling has been implicated in many human diseases including obesity, diabetes, cancer, fatty liver diseases, and neuronal disorders. Here we review recent progress in understanding how mTORC1 （mTOR complex 1） signaling regulates lipid metabolism in the liver.展开更多
Background:Mitochondria are dynamic organelles that constantly change their morphology through fission and fusion processes.Recently,abnormally increased mitochondrial fission has been observed in several types of can...Background:Mitochondria are dynamic organelles that constantly change their morphology through fission and fusion processes.Recently,abnormally increased mitochondrial fission has been observed in several types of can-cer.However,the functional roles of increased mitochondrial fission in lipid metabolism reprogramming in cancer cells remain unclear.This study aimed to explore the role of increased mitochondrial fission in lipid metabolism in hepa-tocellular carcinoma(HCC)cells.Methods:Lipid metabolism was determined by evaluating the changes in the expressions of core lipid metabolic enzymes and intracellular lipid content.The rate of fatty acid oxidation was evaluated by[PH]-labelled oleic acid.The mito-chondrial morphology in HCC cells was evaluated by fluorescent staining.The expression of protein was determined by real-time PCR,imnmunohistochemistry and Western blotting.Results:Activation of mitochondrial fission significantly promoted de novo fatty acid synthesis in HCC cells through upregulating the expression of lipogenic genes fatty acid synthase(FASN),acetyl-CoA carboxylasel(ACCI),and elonga-tion of very long chain fatty acid protein 6(ELOVL6),while suppressed fatty acid oxidation by downregulating carnitine palmitoyl transferase 1A(CPTIA)and acyl-CoA oxidase 1(ACOX1).Consistently,suppressed mitochondrial fission exhibited the opposite effects.Moreover,in vitro and in vivo studies revealed that mitochondrial fission-induced lipid metabolism reprogramming significantly promoted the proliferation and metastasis of HCC cells.Mechanistically,mito-chondrial fission increased the acetylation level of sterol regulatory element-binding protein 1(SREBPI)and peroxisome proliferator-activated receptor coaC-tivator 1 alpha(PGC-1a)by suppressing nicotinamide adenine dinucleotide(NAD+)/Sirtuin 1(SIRTI)signaling.The elevated SREBP1 then upregulated the expression of FASN,ACC1 and ELOVL6 in HCC cells,while PGC-1c/PPARa sup-pressed the expression of CPTIA and ACOXL Conclusions:Increased mitochondrial fission plays a cruc展开更多
Background：A high consumption of fructose leads to hepatic steatosis.About 20-30% of triglycerides are synthesized via de novo lipogenesis.Some studies showed that endoplasmic reticulum stress （ERS） is involved in ...Background：A high consumption of fructose leads to hepatic steatosis.About 20-30% of triglycerides are synthesized via de novo lipogenesis.Some studies showed that endoplasmic reticulum stress （ERS） is involved in this process,while others showed that a lipotoxic environment directly influences ER homeostasis.Here,our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 （XBP-1）,one marker of ERS,on hepatic lipid accumulation stimulated by high fructose.Methods：HepG2 cells were incubated with different concentrations of fructose.Upstream regulators of de novo lipogenesis （i.e.,carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1 c [SREBP-lc]） were measured by polymerase chain reaction and key lipogenic enzymes （acetyl-CoA carboxylase [ACC],fatty acid synthase [FAS],and stearoyl-CoA desaturase-1 [SCD-1]） by Western blotting.The same lipogenesis-associated factors were then evaluated after exposure of HepG2 cells to high fructose followed by the ERS inhibitor tauroursodeoxycholic acid （TUDCA） or the ERS inducer thapsigargin.Finally,the same lipogenesis-associated factors were evaluated in HepG2 cells after XBP-1 upregulation or downregulation through cell transfection.Results：Exposure to high fructose increased triglyceride levels in a dose-and time-dependent manner and significantly increased mRNA levels of SREBP-1c and ChREBP and protein levels ofFAS,ACC,and SCD-1,concomitant with XBP-1 conversion to an active spliced form.Lipogenesis-associated factors induced by high fructose were inhibited by TUDCA and induced by thapsigargin.Triglyceride level in XBP-l-deficient group decreased significantly compared with high-fructose group （4.41 ± 0.54 μmol/g vs.6.52 ± 0.38 μmol/g,P 〈 0.001）,as mRNA expressions of SREBP-1c （2.92 ± 0.46 vs.5.08 ± 0.41,P 〈 0.01） and protein levels of FAS （0.53 ± 0.06 vs.0.85 ± 0.05,P =0.01）,SCD-1 （0.65 ± 0.06 vs.0.90 ± 展开更多
Non-alcoholic fatty liver disease (NAFLD) describes a range of conditions caused by fat deposition within liver cells. Liver fat content reflects the equilibrium between several metabolic pathways involved in triglyce...Non-alcoholic fatty liver disease (NAFLD) describes a range of conditions caused by fat deposition within liver cells. Liver fat content reflects the equilibrium between several metabolic pathways involved in triglyceride synthesis and disposal, such as lipolysis in adipose tissue and de novo lipogenesis, triglyceride esterification, fatty acid oxidation and very-low-density lipoprotein synthesis/secretion in hepatic tissue. In particular, it has been demonstrated that hepatic de novo lipogenesis plays a significant role in NAFLD pathogenesis. It is widely known that the fatty acid composition of the diet influences hepatic lipogenesis along with other metabolic pathways. Therefore, dietary fat may not only be involved in the pathogenesis of hepatic steatosis, but may also prevent and/or reverse hepatic fat accumulation. In this review, major data from the literature about the role of some dietary fats as a potential cause of hepatic fat accumulation or as a potential treatment for NAFLD are described. Moreover, biochemical mechanisms responsible for an increase or decrease in hepatic lipid content are critically analyzed. It is noteworthy that both quantitative and qualitative aspects of dietary fat influence triglyceride deposition in the liver. A high-fat diet or the dietary administration of conjugated linoleic acids induced hepatic steatosis. In contrast, supplementation of the diet with krill oil or pine nut oil helped in the prevention and/or in the treatment of steatotic liver. Quite interesting is the “case” of olive oil, since several studies have often provided different and/or conflicting results in animal models.展开更多
N^(6)-methyladenosine(m^(6)A)modification is critical for m RNA splicing,nuclear export,stability and translation.Fat mass and obesity-associated protein(FTO),the first identified m^(6)A demethylase,is critical for ca...N^(6)-methyladenosine(m^(6)A)modification is critical for m RNA splicing,nuclear export,stability and translation.Fat mass and obesity-associated protein(FTO),the first identified m^(6)A demethylase,is critical for cancer progression.Herein,we developed small-molecule inhibitors of FTO by virtual screening,structural optimization,and bioassay.As a result,two FTO inhibitors namely 18077 and 18097 were identified,which can selectively inhibit demethylase activity of FTO.Specifically,18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells.In addition,18097 reprogrammed the epi-transcriptome of breast cancer cells,particularly for genes related to P53 pathway.18097 increased the abundance of m^(6)A modification of suppressor of cytokine signaling1(SOCS1)m RNA,which recruited IGF2 BP1 to increase m RNA stability of SOCS1 and subsequently activated the P53 signaling pathway.Further,18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma(PPARγ),CCAAT/enhancer-binding protein alpha(C/EBPa),and C/EBPβ.Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells.Collectively,we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.展开更多
This experiment studied hepatic lipogenesis associated with biochemical changes in overfed Landaise Geese and China Xupu geese. Twenty healthy male Landaise geese and 20 healthy male Xupu geese, hatched on the same da...This experiment studied hepatic lipogenesis associated with biochemical changes in overfed Landaise Geese and China Xupu geese. Twenty healthy male Landaise geese and 20 healthy male Xupu geese, hatched on the same day under the same feeding conditions, were selected as experimental animals. The animals were divided into two groups and each breed served as an experimental group. Per goose of per experimental group served for a repeat. Brown rice was selected as test diet. After overfeeding for 21 d and then slaughtering, the biochemical changes of hepatic lipogenesis in the genetic susceptibility to fatty liver were evaluated. These results showed that （1） the weight of fatty liver of the two breeds of geese were 801 and 375 g （P〈0.05）, respectively. There were no differences on the abdominal fat pat, filet total and filet pectoralis major in the two breeds experimental of the geese group （P〈0.05） and no difference on body and filet skin plus subcutaneous adipose tissue （P〉0.05） was found; （2） in these two breeds of geese, there were no differences on very-lowdensity lipoprotein （VLDL）, cholesteryl esters （CE） （P〈0.05）, free cholesterol （FC）, triglycerides （TG）, phospholipids （PL） and protein （P 〈 0.05）; （3） there were no differences on activities of malic enzyme （ME）, glucose-6-phosphatedehydrogenase （G6PDH）, acetyl-CoA-carboxylas （ACX）, fatty acid synthase （FAS）, and mRNA level of ME in the two experimental breeds of geese groups （P 〈0.05）; （4） test in Landaise geese group showed that there was no significant correlation with the specific enzymatic activities, while in Xupu geese group, the liver weight was negatively correlated to the specific activity of ACX and positively to that of ME; （5） in these overfed geese, ME activity appeared to be a major factor involved in the genetic susceptibility to hepatic steatosis and it determined the hepatic lipogenesis capacity.展开更多
Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often...Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low transcytosis.Here,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@V-NPs.With the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice.The combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy mice.Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.展开更多
文摘Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease(NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors(PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation(mitochondrial and peroxisomal)and microsomal omega-oxidation, being markedly decreased by high-fat(HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.
文摘Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols(i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids(i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates(i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.
基金Supported by A concept award from the Department of Defense (DOD) Breast Cancer Research Program, No. W81XWH10-1-0624a research grant from National Institutes of Health, No. GM071475
文摘Alteration of lipid metabolism has been increasingly recognized as a hallmark of cancer cells. The changes of expression and activity of lipid metabolizing enzymes are directly regulated by the activity of oncogenic signals. The dependence of tumor cells on the dysregulated lipid metabolism suggests that proteins involved in this process are excellent chemotherapeutic targets for cancer treatment. There are currently several drugs under development or in clinical trials that are based on specifically targeting the altered lipid metabolic pathways in cancer cells. Further understanding of dysregulated lipid metabolism and its associated signaling pathways will help us to better design efficient cancer therapeutic strategy.
文摘Hatchery-roared juvenile black sea breams are characterized by a low level of highly unsaturated fatty acids in their bodies, as compared with wild fish. To assess the effect of docosahaxaenoic acid （DHA） on lipegenic and lipelysis enzymes, one-year fish were roared on a casein-based purified diet and a DHA fortified diet （ 1.5% DHA ethyl ester/kg diet） for 60 d, followed with a period of 55 d for starvation. Dietary DHA was effectively incorporated into the fish body. Fortification of DHA depressed activities of glucose-6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase as lipogenic enzymes in the hepatopancroas and intraperitoneal fat body. Carnitine palmitoyltransferase as lipolysis enzyme in the hepatopancreas was active in the DHA fortified fish. Starvation after feeding experiment induced increased carnitine palmitoyltransferase activity in both control and DHA fortified fish and the activity remained higher in the DHA fortified fish, while the monoenes were selectively consumed prior to highly unsaturated fatty acids. These results indicated that dietary DHA depressed lipogenesis and activated lipolysis.
文摘AIM To investigate protective effects and molecular mechanisms of green tea polyphenols(GTP) on nonalcoholic fatty liver disease(NAFLD) in Zucker fatty(ZF) rats.METHODS Male ZF rats were fed a high-fat diet(HFD) for 2 wk then treated with GTP(200 mg/kg) or saline(5 m L/kg) for 8 wk, with Zucker lean rat as their control. At the end of experiment, serum and liver tissue were collected for measurement of metabolic parameters, alanine aminotransferase(ALT) and aspartate aminotransferase(AST), inflammatory cytokines and hepatic triglyceride and liver histology. Immunoblotting was used to detect phosphorylation of AMP-activated protein kinase(AMPK) acetyl-Co A carboxylase(ACC), and sterol regulatory element-binding protein 1c(SREBP1c). RESULTS Genetically obese ZF rats on a HFD presented with metabolic features of hepatic pathological changes comparable to human with NAFLD. GTP intervention decreased weight gain(10.1%, P = 0.052) and significantly lowered visceral fat(31.0%, P < 0.01). Compared with ZF-controls, GTP treatment significantly reduced fasting serum insulin, glucose and lipids levels. Reduction in serum ALT and AST levels(both P < 0.01) were observed in GTP-treated ZF rats. GTP treatment also attenuated the elevated TNFα and IL-6 in the circulation. The increased hepatic TG accumulation and cytoplasmic lipid droplet were attenuated by GTP treatment, associated with significantly increased expression of AMPK-Thr172(P < 0.05) and phosphorylated ACC and SREBP1c(both P < 0.05), indicating diminished hepatic lipogenesis and triglycerides out flux from liver in GTP treated rats. CONCLUSION The protective effects of GTP against HFD-induced NAFLD in genetically obese ZF rats are positively correlated to reduction in hepatic lipogenesis through upregulating the AMPK pathway.
文摘The mechanistic target of rapamycin （mTOR） signaling pathway regulates many metabolic and physiological processes in different organs or tissues. DysregulaUon of mTOR signaling has been implicated in many human diseases including obesity, diabetes, cancer, fatty liver diseases, and neuronal disorders. Here we review recent progress in understanding how mTORC1 （mTOR complex 1） signaling regulates lipid metabolism in the liver.
基金supported by the National Natural Sci-ence Foundation of China(81772618),the Young Elite Scientist Sponsorship Program by CAST(2018QNRC001),and the State Key Laboratory of Cancer Biology Project(CBSKL2019ZZ26).
文摘Background:Mitochondria are dynamic organelles that constantly change their morphology through fission and fusion processes.Recently,abnormally increased mitochondrial fission has been observed in several types of can-cer.However,the functional roles of increased mitochondrial fission in lipid metabolism reprogramming in cancer cells remain unclear.This study aimed to explore the role of increased mitochondrial fission in lipid metabolism in hepa-tocellular carcinoma(HCC)cells.Methods:Lipid metabolism was determined by evaluating the changes in the expressions of core lipid metabolic enzymes and intracellular lipid content.The rate of fatty acid oxidation was evaluated by[PH]-labelled oleic acid.The mito-chondrial morphology in HCC cells was evaluated by fluorescent staining.The expression of protein was determined by real-time PCR,imnmunohistochemistry and Western blotting.Results:Activation of mitochondrial fission significantly promoted de novo fatty acid synthesis in HCC cells through upregulating the expression of lipogenic genes fatty acid synthase(FASN),acetyl-CoA carboxylasel(ACCI),and elonga-tion of very long chain fatty acid protein 6(ELOVL6),while suppressed fatty acid oxidation by downregulating carnitine palmitoyl transferase 1A(CPTIA)and acyl-CoA oxidase 1(ACOX1).Consistently,suppressed mitochondrial fission exhibited the opposite effects.Moreover,in vitro and in vivo studies revealed that mitochondrial fission-induced lipid metabolism reprogramming significantly promoted the proliferation and metastasis of HCC cells.Mechanistically,mito-chondrial fission increased the acetylation level of sterol regulatory element-binding protein 1(SREBPI)and peroxisome proliferator-activated receptor coaC-tivator 1 alpha(PGC-1a)by suppressing nicotinamide adenine dinucleotide(NAD+)/Sirtuin 1(SIRTI)signaling.The elevated SREBP1 then upregulated the expression of FASN,ACC1 and ELOVL6 in HCC cells,while PGC-1c/PPARa sup-pressed the expression of CPTIA and ACOXL Conclusions:Increased mitochondrial fission plays a cruc
文摘Background：A high consumption of fructose leads to hepatic steatosis.About 20-30% of triglycerides are synthesized via de novo lipogenesis.Some studies showed that endoplasmic reticulum stress （ERS） is involved in this process,while others showed that a lipotoxic environment directly influences ER homeostasis.Here,our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 （XBP-1）,one marker of ERS,on hepatic lipid accumulation stimulated by high fructose.Methods：HepG2 cells were incubated with different concentrations of fructose.Upstream regulators of de novo lipogenesis （i.e.,carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1 c [SREBP-lc]） were measured by polymerase chain reaction and key lipogenic enzymes （acetyl-CoA carboxylase [ACC],fatty acid synthase [FAS],and stearoyl-CoA desaturase-1 [SCD-1]） by Western blotting.The same lipogenesis-associated factors were then evaluated after exposure of HepG2 cells to high fructose followed by the ERS inhibitor tauroursodeoxycholic acid （TUDCA） or the ERS inducer thapsigargin.Finally,the same lipogenesis-associated factors were evaluated in HepG2 cells after XBP-1 upregulation or downregulation through cell transfection.Results：Exposure to high fructose increased triglyceride levels in a dose-and time-dependent manner and significantly increased mRNA levels of SREBP-1c and ChREBP and protein levels ofFAS,ACC,and SCD-1,concomitant with XBP-1 conversion to an active spliced form.Lipogenesis-associated factors induced by high fructose were inhibited by TUDCA and induced by thapsigargin.Triglyceride level in XBP-l-deficient group decreased significantly compared with high-fructose group （4.41 ± 0.54 μmol/g vs.6.52 ± 0.38 μmol/g,P 〈 0.001）,as mRNA expressions of SREBP-1c （2.92 ± 0.46 vs.5.08 ± 0.41,P 〈 0.01） and protein levels of FAS （0.53 ± 0.06 vs.0.85 ± 0.05,P =0.01）,SCD-1 （0.65 ± 0.06 vs.0.90 ±
文摘Non-alcoholic fatty liver disease (NAFLD) describes a range of conditions caused by fat deposition within liver cells. Liver fat content reflects the equilibrium between several metabolic pathways involved in triglyceride synthesis and disposal, such as lipolysis in adipose tissue and de novo lipogenesis, triglyceride esterification, fatty acid oxidation and very-low-density lipoprotein synthesis/secretion in hepatic tissue. In particular, it has been demonstrated that hepatic de novo lipogenesis plays a significant role in NAFLD pathogenesis. It is widely known that the fatty acid composition of the diet influences hepatic lipogenesis along with other metabolic pathways. Therefore, dietary fat may not only be involved in the pathogenesis of hepatic steatosis, but may also prevent and/or reverse hepatic fat accumulation. In this review, major data from the literature about the role of some dietary fats as a potential cause of hepatic fat accumulation or as a potential treatment for NAFLD are described. Moreover, biochemical mechanisms responsible for an increase or decrease in hepatic lipid content are critically analyzed. It is noteworthy that both quantitative and qualitative aspects of dietary fat influence triglyceride deposition in the liver. A high-fat diet or the dietary administration of conjugated linoleic acids induced hepatic steatosis. In contrast, supplementation of the diet with krill oil or pine nut oil helped in the prevention and/or in the treatment of steatotic liver. Quite interesting is the “case” of olive oil, since several studies have often provided different and/or conflicting results in animal models.
基金supported by the National Natural Science Foundation of China(Grant Nos.82173833,81973343,21877134,22077143,81672608,81974435 and 31801197)The International Cooperation Project of the Science and Technology Planning Project of Guangdong Province,China(No.2021A0505030029)+7 种基金the Open Program of Shenzhen Bay Laboratory(No.SZBL202009051006,China)the Science Foundation of Guangzhou City(201904020023,China)Fundamental Research Funds for Hainan University(KYQD(ZR)-21031,China)the Fundamental Research Funds for the Central Universities(19ykzd24 and 19ykpy130,Sun Yat-sen University,China)the Guangdong Provincial Key Laboratory of Construction Foundation(No.2017B030314030,China)the Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery(2019B030301005,China)the Guangdong Basic and Applied Basic Research Foundation(No.2020A1515010291,China)。
文摘N^(6)-methyladenosine(m^(6)A)modification is critical for m RNA splicing,nuclear export,stability and translation.Fat mass and obesity-associated protein(FTO),the first identified m^(6)A demethylase,is critical for cancer progression.Herein,we developed small-molecule inhibitors of FTO by virtual screening,structural optimization,and bioassay.As a result,two FTO inhibitors namely 18077 and 18097 were identified,which can selectively inhibit demethylase activity of FTO.Specifically,18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells.In addition,18097 reprogrammed the epi-transcriptome of breast cancer cells,particularly for genes related to P53 pathway.18097 increased the abundance of m^(6)A modification of suppressor of cytokine signaling1(SOCS1)m RNA,which recruited IGF2 BP1 to increase m RNA stability of SOCS1 and subsequently activated the P53 signaling pathway.Further,18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma(PPARγ),CCAAT/enhancer-binding protein alpha(C/EBPa),and C/EBPβ.Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells.Collectively,we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.
文摘This experiment studied hepatic lipogenesis associated with biochemical changes in overfed Landaise Geese and China Xupu geese. Twenty healthy male Landaise geese and 20 healthy male Xupu geese, hatched on the same day under the same feeding conditions, were selected as experimental animals. The animals were divided into two groups and each breed served as an experimental group. Per goose of per experimental group served for a repeat. Brown rice was selected as test diet. After overfeeding for 21 d and then slaughtering, the biochemical changes of hepatic lipogenesis in the genetic susceptibility to fatty liver were evaluated. These results showed that （1） the weight of fatty liver of the two breeds of geese were 801 and 375 g （P〈0.05）, respectively. There were no differences on the abdominal fat pat, filet total and filet pectoralis major in the two breeds experimental of the geese group （P〈0.05） and no difference on body and filet skin plus subcutaneous adipose tissue （P〉0.05） was found; （2） in these two breeds of geese, there were no differences on very-lowdensity lipoprotein （VLDL）, cholesteryl esters （CE） （P〈0.05）, free cholesterol （FC）, triglycerides （TG）, phospholipids （PL） and protein （P 〈 0.05）; （3） there were no differences on activities of malic enzyme （ME）, glucose-6-phosphatedehydrogenase （G6PDH）, acetyl-CoA-carboxylas （ACX）, fatty acid synthase （FAS）, and mRNA level of ME in the two experimental breeds of geese groups （P 〈0.05）; （4） test in Landaise geese group showed that there was no significant correlation with the specific enzymatic activities, while in Xupu geese group, the liver weight was negatively correlated to the specific activity of ACX and positively to that of ME; （5） in these overfed geese, ME activity appeared to be a major factor involved in the genetic susceptibility to hepatic steatosis and it determined the hepatic lipogenesis capacity.
基金supported by the National Natural Science Foundation of China(32171381 and 81973254)the National Innovation of Science and Technology-2030(Program of Brain Science and Brain-Inspired Intelligence Technology)grant(2021ZD0204004,China)+1 种基金Jiangsu Key Laboratory of Neuropsychiatric Diseases Research Major Program(No.ZZ2101,China)the Priority Academic Program Development of the Jiangsu Higher Education Institutes(PAPD),Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases,and the Suzhou Science and Technology Development Project(No.SJC2022021,China).
文摘Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low transcytosis.Here,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@V-NPs.With the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice.The combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy mice.Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.
