BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a global health issue that is correlated with obesity and oxidative stress.AIM To evaluate the anti-NAFLD effect of papaya in high fat diet induced obesity in rats...BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a global health issue that is correlated with obesity and oxidative stress.AIM To evaluate the anti-NAFLD effect of papaya in high fat diet induced obesity in rats.METHODS Four-week-old male Sprague-Dawley rats were divided into four groups after 1 wk of acclimatization:Group 1 was the rats fed a normal diet(C);group 2 was the rats fed a high fat diet(HFD);group 3 was the rats fed a HFD with 0.5 mL of papaya juice/100 g body weight(HFL),and group 4 was the rats fed a HFD with 1 mL of papaya juice/100 g body weight(HFH)for 12 wk.At the end of the treatment,blood and tissue samples were collected for biochemical analyses and histological assessment.RESULTS The results of the HFH group showed significantly reduced body weight(HFH vs HFD,P<0.01),decreased NAFLD score(HFH vs HFD,P<0.05),and reduced hepatic total cholesterol(HFL vs HFD,P<0.01;HFH vs HFD,P<0.001),hepatic triglyceride(HFH vs HFD,P<0.05),malondialdehyde(HFL,HFH vs HFD,P<0.001),tumour necrosis factor-α(HFH vs HFD,P<0.05)and interleukin-6(HFH vs HFD,P<0.05)when compared to the HFD group.However,the liver weight showed no significant difference among the groups.The activities of catalase and superoxide dismutase significantly increased in HFH when compared with the HFD group(P<0.05 and P<0.001,respectively).The suppression of transcriptional factors of hepatic lipogenesis,including sterol regulatory elementbinding protein 1c and fatty acid synthase,were observed in the papaya treated group(HFH vs HFD,P<0.05).These beneficial effects of papaya against HFDinduced NAFLD are through lowering hepatic lipid accumulation,suppressing the lipogenic pathway,improving the balance of antioxidant status,and lowering systemic inflammation.CONCLUSION These current results provide experimental-based evidence suggesting papaya is an efficacious medicinal fruit for use in the prevention or treatment of NAFLD.展开更多
AIM:To study,in intact male transgenic mice,the effects of three diets based on olive oil and olive oil diet supplemented with lovastatin and orlistat on hepatic lipogenic enzymes expression,considered markers of cell...AIM:To study,in intact male transgenic mice,the effects of three diets based on olive oil and olive oil diet supplemented with lovastatin and orlistat on hepatic lipogenic enzymes expression,considered markers of cell proliferation.METHODS:Forty ApcMin/+mice were randomly divided into 4 groups and fed for 10 wk:olive oil(OO)group,n=10 animals received a diet with olive oil 12%;olive oil plus lovastatin(LOVA)group,n=10 animals received the same diet with olive oil supplemented with lovastatin 5 mg/kg;olive oil plus orlistat(OR)group,n=10 animals fed the diet with olive oil supplemented with orlistat 50 mg/kg and SD group,n=10 animals fed a standard diet.The activity of lipogenic enzymes and their gene expression were evaluated by radiomet-ric and real-time reverse transcription-polymerase chain reaction assay,respectively.RESULTS:After 10 wk of dietary treatment,the body weight was no different among animal groups(21.3±3.1 g for standard group,22.1±3.6 g for OO group,22.0±3.2 g for LOVA group and 20.7±3.4 g for OR group,data expressed as mean±SD),observing a generalized well-being in all animals.All the dietary managed treated groups presented significantly reduced hepatic levels of fatty acid synthase,farnesyl pyrophosphate synthase and 3-hydroxyl-3-methyl-glutaryl CoA reductase activity and gene expression when compared with the mice fed the standard diet.To evaluate cell proliferation in the liver of treated mice,the levels of cyclin E mRNA have been measured,demonstrating a significant reduction of cyclin E gene expression in all treated groups.Evidence of reduced hepatic cell proliferation was present overall in OO group mice.CONCLUSION:We confirm the role of lipogenic enzymes as markers of cell proliferation,suggesting that appropriate dietary management alone or with drugs can be a feasible approach to counteract hepatic cell proliferation in mice.展开更多
There is growing evidence that metabolic alterations play an important role in cancer development and progression.The metabolism of cancer cells is reprogrammed in order to support their rapid proliferation.Elevated f...There is growing evidence that metabolic alterations play an important role in cancer development and progression.The metabolism of cancer cells is reprogrammed in order to support their rapid proliferation.Elevated fatty acid synthesis is one of the most important aberrations of cancer cell metabolism.An enhancement of fatty acids synthesis is required both for carcinogenesis and cancer cell survival,as inhibition of key lipogenic enzymes slows down the growth of tumor cells and impairs their survival.Based on the data that serum fatty acid synthase(FASN),also known as oncoantigen 519,is elevated in patients with certain types of cancer,its serum level was proposed as a marker of neoplasia.This review aims to demonstrate the changes in lipid metabolism and other metabolic processes associated with lipid metabolism in pancreatic ductal adenocarcinoma(PDAC),the most common pancreatic neoplasm,characterized by high mortality.We also addressed the influence of some oncogenic factors and tumor suppressors on pancreatic cancer cell metabolism.Additionally the review discusses the potential role of elevated lipid synthesis in diagnosis and treatment of pancreatic cancer.In particular,FASN is a viable candidate for indicator of pathologic state,marker of neoplasia,as well as,pharmacological treatment target in pancreatic cancer.Recent research showed that,in addition to lipogenesis,certain cancer cells can use fatty acids from circulation,derived from diet(chylomicrons),synthesized in liver,or released from adipose tissue for their growth.Thus,the interactions between de novo lipogenesis and uptake of fatty acids from circulation by PDAC cells require further investigation.展开更多
The function of exogenous alanine(Ala)in regulating biomass accumulation,lipid production,photosynthesis,and respiration in Chlorella pyrenoidosa was studied.Result shows that the supplementation of Ala increased C.py...The function of exogenous alanine(Ala)in regulating biomass accumulation,lipid production,photosynthesis,and respiration in Chlorella pyrenoidosa was studied.Result shows that the supplementation of Ala increased C.pyrenoidosa biomass and lipid production in an 8-d batch culture.The concentration of 10 mmol/L of Ala was optimum and increased the microalgal cell biomass and lipid content by 39.3%and 21.4%,respectively,compared with that in the control(0-mmol/L Ala).Ala supplementation reduced photosynthetic activity while boosting respiratory activity and pyruvate levels,indicating that C.pyrenoidosa used exogenous Ala for biomass accumulation through the respiratory metabolic process.The accelerated respiratory metabolism due to Ala supplementation elevated the substrate pool and improved the lipogenic gene expression,promoting lipid production at last.This study provided a novel method for increasing biomass accumulation and lipid production and elucidated the role of Ala in regulating lipid production.展开更多
Oleaginous fungi can convert a variety of substrates into lipids,frequently containing(20-70%,w/w)of their cell dry weight(CDW),which positions them as promising candidates for sustainable lipid production.However,the...Oleaginous fungi can convert a variety of substrates into lipids,frequently containing(20-70%,w/w)of their cell dry weight(CDW),which positions them as promising candidates for sustainable lipid production.However,the interplay of calcium(Ca^(2+))in regulating lipid accumulation remains unclear.Therefore,the effect of different Ca^(2+)concentrations on the oleaginous capacity of Mucor circinelloides strain WJ11 was evaluated.Hence,WJ11 was fermented for 96 h using different Ca^(2+)levels.Maximum CDW(17.2 g/L)and lipid yield(42%,w/w)were achieved at 2.5 and 0.3 g/L Ca^(2+),respectively,compared to 15.8 g/L CDW and(34%,w/w)lipid content in the control(0.1 g/L Ca^(2+)).High Ca^(2+)levels(12.5-20 g/L)improved the production of certain fatty acids(FAs),whereas optimal levels favoured the accumulation of stearic acid(C18:0)andγ-linolenic acid(C18:3)at designated time intervals.Furthermore,the calcineurin catalytic subunits(CnaA,CnaB,and CnaC)and regulatory subunit(CAR1)were significantly upregulated after 12 h of fermentation.Additionally,lipogenic enzyme activity analysis of key genes involved in lipid biosynthesis exhibited upregulation at different Ca^(2+)concentrations.These findings indicated that raised Ca^(2+)levels can significantly boost lipid production in industrial fermentations.This study is the first to investigate the role of Ca^(2+)in the oleaginous fungus M.circinelloides,providing new avenues into the integrated functions of Ca^(2+)and its signaling pathways in lipid metabolism,particularly in oleaginous fungi.展开更多
Disrupted lipogenic signaling and steatosis are key features of alcohol-associated liver disease(ALD).A-kinase anchoring protein 12(AKAP12)is a scaffolding partner of the cAMP-dependent protein kinase,PKA that control...Disrupted lipogenic signaling and steatosis are key features of alcohol-associated liver disease(ALD).A-kinase anchoring protein 12(AKAP12)is a scaffolding partner of the cAMP-dependent protein kinase,PKA that controls its spatiotemporal localization.Activation of PKA by cAMP inhibits lipogenesis and facilitates fatty acid oxidation(FAO).The goal of this work is to examine how AKAP12’s PKA-anchoring ability regulates outcomes of alcohol-associated steatosis.Crosslinking proteomics identified PKA and its lipogenic substrates as interacting partners of AKAP12.Alcohol exposure diminished AKAP12’s interaction with PKA regulatory subunits and PKA substrates,acetyl CoA carboxylase(ACC1),pyruvate dehydrogenase(PDHA)and adipose triglyceride lipase(ATGL).Alcohol inhibited PKA activity and increased triglyceride content in human hepatocytes.Forced expression of AKAP12 restored alcohol suppressed PKA activation and inhibited lipid accumulation,whereas silencing had the reverse effect.Since AKAP12 sustained PKA activity,we evaluated whether the AKAP12-PKA scaffold was important in lipid homeostasis.Inhibition of AKAP12-PKA interaction by CRISPR deletion of AKAP12’s PKA binding domain in cultured hepatocytes or in mouse models of ALD dramatically suppressed PKA activity,enhanced ACC1 activity demonstrated by reduced inhibitory phosphorylation,increased lipid accumulation and reduced FAO in hepatocytes.Overexpression of AKAP12 in mouse livers sustained PKA activation,diminished basal and alcohol potentiated triglyceride content,and regulated inflammatory signaling altered by alcohol.Mechanistically,we discovered that alcohol enhanced the inhibitory activity of a kinase,serine/threonine-protein kinase 25(STK25)on PKA that regulated its interaction with AKAP12.In conclusion,the AKAP12-PKA scaffold controls lipogenic signaling,disruption of which favors steatosis during ALD.展开更多
The role of fatty acid metabolism,including both anabolic and catabolic reactions in cancer has gained increas-ing attention in recent years.Many studies have shown that aberrant expression of the genes involved in fa...The role of fatty acid metabolism,including both anabolic and catabolic reactions in cancer has gained increas-ing attention in recent years.Many studies have shown that aberrant expression of the genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes including metastasis,therapeutic resistance and relapse.Such phenotypes are also strongly associated with the presence of a small percentage of unique cells among the total tumor cell population.This distinct group of cells may have the ability to self-renew and propagate or may be able to develop resistance to cancer therapies independent of genetic alterations.Therefore,these cells are referred to as cancer stem cells/tumor-initiating cells/drug-tolerant persisters,which are often refractory to cancer treatment and difficult to target.Moreover,interconversion between cancer cells and cancer stem cells/tumor-initiating cells/drug-tolerant persisters may occur and makes treatment even more challenging.This review highlights recent findings on the relationship between fatty acid metabolism,cancer stemness and therapeutic resistance and prompts discussion about the potential mechanisms by which fatty acid metabolism regulates the fate of cancer cells and therapeutic resistance.展开更多
基金Supported by National Research Council of Thailand,No.R2560B137(to Tunsophon S)and No.2562/20(to Deenin W)Thailand Research Fund,No.RDG5820017(to Tunsophon S).
文摘BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a global health issue that is correlated with obesity and oxidative stress.AIM To evaluate the anti-NAFLD effect of papaya in high fat diet induced obesity in rats.METHODS Four-week-old male Sprague-Dawley rats were divided into four groups after 1 wk of acclimatization:Group 1 was the rats fed a normal diet(C);group 2 was the rats fed a high fat diet(HFD);group 3 was the rats fed a HFD with 0.5 mL of papaya juice/100 g body weight(HFL),and group 4 was the rats fed a HFD with 1 mL of papaya juice/100 g body weight(HFH)for 12 wk.At the end of the treatment,blood and tissue samples were collected for biochemical analyses and histological assessment.RESULTS The results of the HFH group showed significantly reduced body weight(HFH vs HFD,P<0.01),decreased NAFLD score(HFH vs HFD,P<0.05),and reduced hepatic total cholesterol(HFL vs HFD,P<0.01;HFH vs HFD,P<0.001),hepatic triglyceride(HFH vs HFD,P<0.05),malondialdehyde(HFL,HFH vs HFD,P<0.001),tumour necrosis factor-α(HFH vs HFD,P<0.05)and interleukin-6(HFH vs HFD,P<0.05)when compared to the HFD group.However,the liver weight showed no significant difference among the groups.The activities of catalase and superoxide dismutase significantly increased in HFH when compared with the HFD group(P<0.05 and P<0.001,respectively).The suppression of transcriptional factors of hepatic lipogenesis,including sterol regulatory elementbinding protein 1c and fatty acid synthase,were observed in the papaya treated group(HFH vs HFD,P<0.05).These beneficial effects of papaya against HFDinduced NAFLD are through lowering hepatic lipid accumulation,suppressing the lipogenic pathway,improving the balance of antioxidant status,and lowering systemic inflammation.CONCLUSION These current results provide experimental-based evidence suggesting papaya is an efficacious medicinal fruit for use in the prevention or treatment of NAFLD.
文摘AIM:To study,in intact male transgenic mice,the effects of three diets based on olive oil and olive oil diet supplemented with lovastatin and orlistat on hepatic lipogenic enzymes expression,considered markers of cell proliferation.METHODS:Forty ApcMin/+mice were randomly divided into 4 groups and fed for 10 wk:olive oil(OO)group,n=10 animals received a diet with olive oil 12%;olive oil plus lovastatin(LOVA)group,n=10 animals received the same diet with olive oil supplemented with lovastatin 5 mg/kg;olive oil plus orlistat(OR)group,n=10 animals fed the diet with olive oil supplemented with orlistat 50 mg/kg and SD group,n=10 animals fed a standard diet.The activity of lipogenic enzymes and their gene expression were evaluated by radiomet-ric and real-time reverse transcription-polymerase chain reaction assay,respectively.RESULTS:After 10 wk of dietary treatment,the body weight was no different among animal groups(21.3±3.1 g for standard group,22.1±3.6 g for OO group,22.0±3.2 g for LOVA group and 20.7±3.4 g for OR group,data expressed as mean±SD),observing a generalized well-being in all animals.All the dietary managed treated groups presented significantly reduced hepatic levels of fatty acid synthase,farnesyl pyrophosphate synthase and 3-hydroxyl-3-methyl-glutaryl CoA reductase activity and gene expression when compared with the mice fed the standard diet.To evaluate cell proliferation in the liver of treated mice,the levels of cyclin E mRNA have been measured,demonstrating a significant reduction of cyclin E gene expression in all treated groups.Evidence of reduced hepatic cell proliferation was present overall in OO group mice.CONCLUSION:We confirm the role of lipogenic enzymes as markers of cell proliferation,suggesting that appropriate dietary management alone or with drugs can be a feasible approach to counteract hepatic cell proliferation in mice.
基金Supported by Medical University of Gdansk Grants ST-41,ST-40
文摘There is growing evidence that metabolic alterations play an important role in cancer development and progression.The metabolism of cancer cells is reprogrammed in order to support their rapid proliferation.Elevated fatty acid synthesis is one of the most important aberrations of cancer cell metabolism.An enhancement of fatty acids synthesis is required both for carcinogenesis and cancer cell survival,as inhibition of key lipogenic enzymes slows down the growth of tumor cells and impairs their survival.Based on the data that serum fatty acid synthase(FASN),also known as oncoantigen 519,is elevated in patients with certain types of cancer,its serum level was proposed as a marker of neoplasia.This review aims to demonstrate the changes in lipid metabolism and other metabolic processes associated with lipid metabolism in pancreatic ductal adenocarcinoma(PDAC),the most common pancreatic neoplasm,characterized by high mortality.We also addressed the influence of some oncogenic factors and tumor suppressors on pancreatic cancer cell metabolism.Additionally the review discusses the potential role of elevated lipid synthesis in diagnosis and treatment of pancreatic cancer.In particular,FASN is a viable candidate for indicator of pathologic state,marker of neoplasia,as well as,pharmacological treatment target in pancreatic cancer.Recent research showed that,in addition to lipogenesis,certain cancer cells can use fatty acids from circulation,derived from diet(chylomicrons),synthesized in liver,or released from adipose tissue for their growth.Thus,the interactions between de novo lipogenesis and uptake of fatty acids from circulation by PDAC cells require further investigation.
基金Supported by the National Natural Science Foundation of China(Nos.32002411,42276189)the Innovation and Entrepreneurship Project for College Students of Hohai University(No.2022102941027)the Jiangsu Innovation Center for Marine Bioresources(No.822153216)。
文摘The function of exogenous alanine(Ala)in regulating biomass accumulation,lipid production,photosynthesis,and respiration in Chlorella pyrenoidosa was studied.Result shows that the supplementation of Ala increased C.pyrenoidosa biomass and lipid production in an 8-d batch culture.The concentration of 10 mmol/L of Ala was optimum and increased the microalgal cell biomass and lipid content by 39.3%and 21.4%,respectively,compared with that in the control(0-mmol/L Ala).Ala supplementation reduced photosynthetic activity while boosting respiratory activity and pyruvate levels,indicating that C.pyrenoidosa used exogenous Ala for biomass accumulation through the respiratory metabolic process.The accelerated respiratory metabolism due to Ala supplementation elevated the substrate pool and improved the lipogenic gene expression,promoting lipid production at last.This study provided a novel method for increasing biomass accumulation and lipid production and elucidated the role of Ala in regulating lipid production.
基金supported by the National Natural Science Foundation of China under Grant(No.31972851)the Shandong Province Small and Medium Enterprises Innovation Ability Enhancement Project(grant No.2021TSGC1281 and 2023TSGC0050)supporting this work through project number(TU-DSPP-2024-186).
文摘Oleaginous fungi can convert a variety of substrates into lipids,frequently containing(20-70%,w/w)of their cell dry weight(CDW),which positions them as promising candidates for sustainable lipid production.However,the interplay of calcium(Ca^(2+))in regulating lipid accumulation remains unclear.Therefore,the effect of different Ca^(2+)concentrations on the oleaginous capacity of Mucor circinelloides strain WJ11 was evaluated.Hence,WJ11 was fermented for 96 h using different Ca^(2+)levels.Maximum CDW(17.2 g/L)and lipid yield(42%,w/w)were achieved at 2.5 and 0.3 g/L Ca^(2+),respectively,compared to 15.8 g/L CDW and(34%,w/w)lipid content in the control(0.1 g/L Ca^(2+)).High Ca^(2+)levels(12.5-20 g/L)improved the production of certain fatty acids(FAs),whereas optimal levels favoured the accumulation of stearic acid(C18:0)andγ-linolenic acid(C18:3)at designated time intervals.Furthermore,the calcineurin catalytic subunits(CnaA,CnaB,and CnaC)and regulatory subunit(CAR1)were significantly upregulated after 12 h of fermentation.Additionally,lipogenic enzyme activity analysis of key genes involved in lipid biosynthesis exhibited upregulation at different Ca^(2+)concentrations.These findings indicated that raised Ca^(2+)levels can significantly boost lipid production in industrial fermentations.This study is the first to investigate the role of Ca^(2+)in the oleaginous fungus M.circinelloides,providing new avenues into the integrated functions of Ca^(2+)and its signaling pathways in lipid metabolism,particularly in oleaginous fungi.
基金supported by NIH grant R01AA029988(PI:Komal Ramani,Co-I’s-Nirmala Mavila,and Maria Lauda Tomasi).
文摘Disrupted lipogenic signaling and steatosis are key features of alcohol-associated liver disease(ALD).A-kinase anchoring protein 12(AKAP12)is a scaffolding partner of the cAMP-dependent protein kinase,PKA that controls its spatiotemporal localization.Activation of PKA by cAMP inhibits lipogenesis and facilitates fatty acid oxidation(FAO).The goal of this work is to examine how AKAP12’s PKA-anchoring ability regulates outcomes of alcohol-associated steatosis.Crosslinking proteomics identified PKA and its lipogenic substrates as interacting partners of AKAP12.Alcohol exposure diminished AKAP12’s interaction with PKA regulatory subunits and PKA substrates,acetyl CoA carboxylase(ACC1),pyruvate dehydrogenase(PDHA)and adipose triglyceride lipase(ATGL).Alcohol inhibited PKA activity and increased triglyceride content in human hepatocytes.Forced expression of AKAP12 restored alcohol suppressed PKA activation and inhibited lipid accumulation,whereas silencing had the reverse effect.Since AKAP12 sustained PKA activity,we evaluated whether the AKAP12-PKA scaffold was important in lipid homeostasis.Inhibition of AKAP12-PKA interaction by CRISPR deletion of AKAP12’s PKA binding domain in cultured hepatocytes or in mouse models of ALD dramatically suppressed PKA activity,enhanced ACC1 activity demonstrated by reduced inhibitory phosphorylation,increased lipid accumulation and reduced FAO in hepatocytes.Overexpression of AKAP12 in mouse livers sustained PKA activation,diminished basal and alcohol potentiated triglyceride content,and regulated inflammatory signaling altered by alcohol.Mechanistically,we discovered that alcohol enhanced the inhibitory activity of a kinase,serine/threonine-protein kinase 25(STK25)on PKA that regulated its interaction with AKAP12.In conclusion,the AKAP12-PKA scaffold controls lipogenic signaling,disruption of which favors steatosis during ALD.
基金supported in part by funds from the National Institutes of Health R01DE026304 and R01CA220693(to D.K.A.)Ministry of Science and Technology,R.O.C,Special Talents Award(to C.-Y.K).
文摘The role of fatty acid metabolism,including both anabolic and catabolic reactions in cancer has gained increas-ing attention in recent years.Many studies have shown that aberrant expression of the genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes including metastasis,therapeutic resistance and relapse.Such phenotypes are also strongly associated with the presence of a small percentage of unique cells among the total tumor cell population.This distinct group of cells may have the ability to self-renew and propagate or may be able to develop resistance to cancer therapies independent of genetic alterations.Therefore,these cells are referred to as cancer stem cells/tumor-initiating cells/drug-tolerant persisters,which are often refractory to cancer treatment and difficult to target.Moreover,interconversion between cancer cells and cancer stem cells/tumor-initiating cells/drug-tolerant persisters may occur and makes treatment even more challenging.This review highlights recent findings on the relationship between fatty acid metabolism,cancer stemness and therapeutic resistance and prompts discussion about the potential mechanisms by which fatty acid metabolism regulates the fate of cancer cells and therapeutic resistance.
