Progress 02/15/15 to 02/14/18
Outputs
Target Audience:Consumers, in particular persons with fatty liver disease, will benefit from potential health promoting effects of tomato and tomato products, and from increased knowledge of the various biological activities of lycopene and apolycopenoids. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?The project has provided an ideal training environment for PhD students of Tufts School of Nutrition. This project helped greatly two graduate students to understand how dietary components and molecular pathways can influence inflammation and chronic disease development. This project utilizing biochemistry and molecular biology techniques assisted these two students to become research scientist in the field of nutrition and chronic disease prevention. How have the results been disseminated to communities of interest?We have reported our finding in the 2016 Experimental Biology meeting, 2017 AFRI project director meeting, 2017 Experimental Biology meeting and 2017 International Society of Carotenoids symposium, as well as the upcoming 2018 American Nutrition Society meeting in Boston. We have published four manuscripts and submitted another manuscript generated from the project. Our work is highly significant for the dietary tomato prevention of fatty liver disease and obesity-related complications. In particular, our results indicated that dietary tomato powder can restore adiponectin function to normal, and higher gut microbial richness and lower abundance of Clostridium, which opened a new avenue to investigate whether gut microbiome is targeting mechanism for protective effect of tomato powder intervention. We are currently working on other manuscript. What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
The prevalence of non-alcoholic fatty liver disease (NAFLD) is positively associated with the obesity epidemic and the risks for hepatocellular carcinoma (HCC), which is the second leading cause of cancer mortality worldwide. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that has emerged as a key metabolic sensor that links environmental signals to metabolic homeostasis, NAFLD, and to metabolic syndrome-associated HCC. Previous studies have shown that supplementation of tomato carotenoids, such as apo-10'-lycopenoic acid (ALA) which is an oxidized metabolite of apo-10'-lycopenal through lycopene cleavage by beta-carotene-9', 10'-oxygenase, can increase the expression and activity of SIRT1 and impede the development of NAFLD and HCC. Beta-carotene-15,15'-oxygenase (BCO1) and beta-carotene-9',10'-oxygenase (BCO2) metabolize lycopene to biologically active metabolites, which can ameliorate NAFLD. However, whether tomato carotenoids protect against NAFLD and HCC dependent on BCO1/BCO2 and SIRT1 signaling is enigmatic, and the causality between SIRT1 activity and the pathogenesis of NAFLD and HCC remains unknown. The primary objective of this project is to investigate the causal role of systemic SIRT1 activity in the development of NAFLD and HCC, and whether dietary tomato and tomato carotenoids protect against NAFLD and HCC in a BCO1/BCO2 and SIRT1-dependent manner. We investigated the effects of tomato powder (TP containing substantial lycopene (2.3 mg/g)) on NAFLD development and gut microbiome in the absence of both BCO1 and BCO2 in mice. In the 1st project, BCO1-/-/BCO2-/- double knockout mice were fed a high fat diet (HFD) alone or with TP feeding for 24 weeks. TP feeding significantly reduced pathological severity of steatosis and hepatic triglyceride levels in BCO1-/-/BCO2-/- mice (P<0.04 vs. HFD alone). This was associated with increased SIRT1 activity, nicotinamide phosphoribosyltransferase expression and AMPK phosphorylation, and subsequently decreased lipogenesis, hepatic fatty acid uptake, and increasing fatty acid β-oxidation. TP feeding significantly decreased mRNA expression of pro-inflammatory genes in both liver and mesenteric adipose tissue, which were associated with increased plasma adiponectin and hepatic adiponectin receptor-2. Multiplexed 16S rRNA gene sequencing was performed using DNA extracted from cecum fecal samples. TP feeding increased microbial richness and decreased relative abundance of the genus Clostridium. This study demonstrated that dietary TP can inhibit NAFLD independent of carotenoid cleavage enzymes, potentially through increasing SIRT1 activity and adiponectin production and decreasing Clostridium abundance. In the 2nd project, by utilizing SIRT1 homozygous mutation mice ablated of the catalytic activity of SIRT1 (MT) and their corresponding wild type (WT) littermates, we showed that SIRT1 loss-of-function aggravated HFD-induced NAFLD progression, intriguingly, by promoting the mobility of free fatty acid (FFA) from mesenteric adipose tissue (MAT) to the liver. This study revealed a critical role of SIRT1 in preventing NAFLD, and addressed the underlying mechanism that people without 'belly fat' still develop fatty liver when SIRT1 activity decreases due to certain factors such as aging, unhealthy diet, and/or stress. In the 3nd project, both WT and MT mice were treated with hepatic carcinogen diethylnitrosamine, followed by HFD feeding with or without tomato powder (TP, representative of whole tomato) for 34 weeks. Results revealed that TP supplementation significantly reduced liver steatosis in both WT and MT mice through different molecular mechanisms. The protective effect of TP in WT mice was mediated by increasing SIRT1 protein expression and activity, and decreasing hepatic fatty acid binding protein 1 expression and FFA uptake. While in MT mice, TP decreased hepatic fatty acid synthesis through inactivating hepatic acetyl-CoA carboxylase mediated by AMPK phosphorylation, independent of SIRT1. Additionally, TP lowered il-6 mRNA expression in MAT and IL-6 concentration in plasma, as compared with MT mice without TP. In WT mice, dietary TP decreased caspase-1 mediated IL-1β maturation. However, we did not detect significant hepatic inflammatory cell infiltration in both WT and MT mice. Neither the mutation of SIRT1 activity nor TP supplementation altered incidence or multiplicity of HCC in both WT and MT mice. This could be due to the lack of inflammation as a target of TP protection or limited efficacy of SIRT1 in ameliorating HCC development in this mouse model. In the last project, we demonstrated that ALA supplementation at 10 mg/kg diet in WT and MT mice for 34 weeks achieved a comparable effect against NAFLD between WT and MT mice. Unexpectedly, MT mice developed less hepatic tumor multiplicity, as compared with WT mice fed the same dose of ALA. Interestingly, the ablation of SIRT1 activity resulted in increased expression of hepatic nuclear receptors (rxrα, lxrα, pparγ) and vitamin A transporter cd36, and hepatic retinol concentration, but decreased cyclin D1 protein levels, suggesting potential contribution of these nuclear receptors and retinol as well as cell cycle arrest to the reduction of hepatic tumor multiplicity. This study demonstrated that ALA protects against NAFLD and HCC independent of SIRT1 activity and the lack of SIRT1 activity reduced the progression of HCC in mice given HFD and ALA supplementation. In summary, through this work, we first demonstrated the causal role of absence of SIRT1 activity in the pathogenesis of NAFLD, which underscores the key role of SIRT1 in ameliorating NAFLD progression through involving multiple organs. Secondly by exploring an efficient dietary strategy against NAFLD, we demonstrated that dietary TP as a whole food approach acts as an effective disease prevention strategy against NAFLD independent of carotenoid cleavage enzymes (BCO1/BCO2) and SIRT1 activity. Lastly, we demonstrated that lack of SIRT1 activity inhibited HCC development in mice given HFD and ALA supplementation, highlighting the complex regulation of SIRT1 in hepatic tumorigenesis with paradoxical functions as tumor suppressor or tumor promoter.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2018
Citation:
Cheng C, Mioao B, Hu KQ, Fu X and Wang X-D. Apo-10-lycopenoic acid inhibits cancer cell migration and angiogenesis and induces peroxisome proliferator-activated receptor. Journal of Nutritional Biochemistry 56 (2018) 2634
- Type:
Journal Articles
Status:
Published
Year Published:
2017
Citation:
Cheng C, Liu C, Hu KQ, Greenberg A, Wu D, Ausman LM, McBurney MW and Wang X-D. Ablation of systemic SIRT1 activity promotes nonalcoholic fatty liver disease by affecting liver-mesenteric adipose tissue fatty acid mobilization. Biochimica et Biophysica Acta, 1863:2783-2790, 2017
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Aizawa K, Liu C, Veeramachaneni S, Hu KQ, Smith DE, Wang X-D. Tobacco carcinogen (NNK) induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation. International Journal of Cancer, 139(5):1171-81, 2016
- Type:
Journal Articles
Status:
Published
Year Published:
2018
Citation:
Li CC, Liu C, Fu M, Hu KQ, Aizawa K, Cheng J, von Lintig J and Wang X-D. Tomato powder inhibits hepatic steatosis and inflammation potentially through restoring SIRT1 activity and adiponectin function independent of carotenoid cleavage enzymes in mice. Molecular Nutrition Food Research [E-pub ahead of print], 2018.
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Progress 02/15/17 to 02/14/18
Outputs
Target Audience:Consumers, in particular persons with fatty liver disease, will benefit from potential health promoting effects of tomato and tomato products, and from increased knowledge of the various biological activities of lycopene and apolycopenoids. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?The project has provided an ideal training environment for PhD students of Tufts School of Nutrition. This project helped greatly two graduate students to understand how dietary components and molecular pathways can influence inflammation and chronic disease development. This project utilizing biochemistry and molecular biology techniques assisted these two students to become research scientist in the field of nutrition and chronic disease prevention. How have the results been disseminated to communities of interest?In addition to previously published manuscripts and conference presentations, we also plan to report our findings at the upcoming 2018 American Nutrition Society meeting in Boston, MA What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
Our investigation demonstrated that dietary tomato powder effectively inhibited high fat diet-induced nonalcoholic fatty liver disease independent of carotenoid cleavage enzymes. The protective effects of tomato powder involved the regulation of a key enzyme called SIRT1 and its related gene production in adipose tissue. Additionally, we observed that the tomato powder supplementation resulted in a lower relative abundance of the gram-positive bacteria (genus Clostridium) in gut, as compared with the high fat diet alone group. This study opened a new avenue to investigate whether the underlying mechanism of the protective effect of tomato as a whole food is due to influencing the gut microbiome. Interestingly, we also found that apo-10'-lycopenoid, a metabolite of lycopene through cleavage by carotenoid cleavage enzyme in tomato induced cell nuclear receptor (called peroxisome proliferator-activated receptor-gamma) and inhibited angiogenesis and tumor cell migration. This could be one of the potential mechanisms for tomato protecting against tumor development.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2018
Citation:
Li CC, Liu C, Fu M, Hu KQ, Aizawa K, Cheng J, von Lintig J and Wang X-D. Tomato powder inhibits hepatic steatosis and inflammation potentially through restoring SIRT1 activity and adiponectin function independent of carotenoid cleavage enzymes in mice. Molecular Nutrition Food Research [E-pub ahead of print], 2018.
- Type:
Journal Articles
Status:
Published
Year Published:
2018
Citation:
Cheng C, Mioao B, Hu KQ, Fu X and Wang X-D. Apo-10-lycopenoic acid inhibits cancer cell migration and angiogenesis and induces peroxisome proliferator-activated receptor. Journal of Nutritional Biochemistry 56 (2018) 2634
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Progress 02/15/16 to 02/14/17
Outputs
Target Audience:Consumers, in particular persons with fatty liver disease, will benefit from potential health promoting effects of tomato and tomato products, and from increased knowledge of the various biological activities of lycopene and apolycopenoids. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?The project has provided an ideal training environment for Tufts PhD students. In particular, this project helped greatly students to understand how dietary components and molecular pathways can influence inflammation and cancer development. This project utilizing biochemistry and molecular biology techniques will assist individual with great potential to become a scientist in the field of nutrition and cancer prevention. How have the results been disseminated to communities of interest?We will report our finding in the coming 2017 AFRI project director meeting, 2017 Experimental Biology meeting and 2017 International Society of Carotenoids symposium. . Our work will be highly significant for the dietary tomato prevention of fatty liver disease and obesity-related complications. What do you plan to do during the next reporting period to accomplish the goals?We are working on three manuscripts generated from the project. We are currently conducting feeding experiemnts with tomato powder and apo-lycopenoid using Sirt1Y/Y mice and wildtype mouse models. We will demonstrate whether Sirt1 is a moleuclar target for the protective effect of tomato powder and apo-lycopenoid intervention. Our very recent results indicate that dietary tomato powder can restore adiponectin function to normal, and higher gut microbial richness and lower abundance of Clostridium, which pened a new avenue to investigate whether gut microbiome is targeting mechanism for protective effect of tomato powder intervention.
Impacts
What was accomplished under these goals?
Consumption of high-fat diet has been proposed to be one of risk factor for increased prevalence of nonalcoholic fatty liver disease, a major form of chronic liver disease in adults and children. NIFA/AFRI-funded researchers in Tufts University, Boston, MA, provided novel evidence to suggest that under high-fat diet-induced metabolic surplus, the lack of mammalian sirtuin 1 catalytic activity, a highly conserved protein deacetylase, promotes release of fatty acid from adipose tissue into systemic circulation and escalate nonalcoholic fatty liver disease by interfering with lipid homeostasis in both liver and adipose tissue. Additionally, research scientists from Tufts University provided strong evidence demonstrating that dietary tomato powder can inhibit high fat diet-induced hepatic steatosis and inflammatory responses independent of carotenoid cleavage enzymes, potentially through restoring adiponectin function to normal, and higher gut microbial richness and lower abundance of Clostridium. This study opened a new avenue to investigate whether gut microbiome is targeting mechanism for protective effect of tomato powder intervention. Objectives: Objective 1) To investigate the biological function of apocarotenoids from tomatoes and tomato products or from enzymatic cleavage of lycopene by mammalian carotenoid oxygenases as important protective agents against the high fat diet-induced inflammation and tumorigenesis We investigated the effects of whole tomato (tomato powder, TP) supplementation on HFD-induced hepatic steatosis and inflammation in BCO1-/-/BCO2-/- double knockout mice. Six-week-old male BCO1-/-/BCO2-/- double knockout (KO) mice were fed a HFD (59% of calories from lard, n=9) alone or with lycopene rich-TP supplementation (41.9 g/kg diet, HFD+TP, n=9) for 24 weeks. Result showed that dietary TP significantly reduced HFD-induced hepatic steatosis and triglyceride (TG) content in the liver (27% reduction), which was associated with significantly increased SIRT1 deacetylase activity, higher expression of nicotinamide phosphoribosyltransferase, and increased AMPK phosphorylation. TP supplementation down-regulated lipogenesis marker acetyl-CoA carboxylase and induced peroxisome proliferator-activated receptor-α related genes in the liver which down-regulates fatty acid uptake receptor gene (Cd36) and the key enzyme of TG synthesis (diglyceride acyltransferaseand-1) and, increases fatty acid β-oxidation markers (carnitine palmitoyltransferase I and acyl-CoA oxidase 1). In addition, TP supplementation decreased mRNA expressions of pro-inflammatory genes [tumor necrosis factor-α, interleukin (Il)-1β, and Il-6] in liver and increased mRNA expressions of adiponectin visceral adipose tissue (VAT) as well as elevation of plasma levels of adiponectin in the HFD+TP group. Furthermore, we extracted genomic DNA from fecal sample (cecum) and explored the possibility that the TP supplementation is capable of altering the gut microbiome in the present study. For pyrosequencing, amplification of genomic DNA was performed using barcoded primers, which targeted the V1 to V3 region of the bacterial 16S rRNA gene. We found that the observed diversity richness (OTUs (operational taxonomic units)), and estimated OUT richness (ACE), were significantly higher in the HFD+TP group, as compared with the HFD alone group, indicating that dietary TP supplementation increased microbial richness in HFD-fed mice. Additionally, we did not found any difference on the relative abundance of both gram-positive (mainly Firmicutes) and gram-negative (mainly Bacteroidetes) bacteria among the groups, but the TP supplementation resulted in a relative lower abundance of Clostridium. Taken together, our results indicate that dietary TP can inhibit HFD-induced hepatic steatosis and inflammatory responses independent of carotenoid cleavage enzymes, potentially through restoring adiponectin function to normal, and higher gut microbial richness and lower abundance of Clostridium. Objective 2) To determine the ability of apocarotenoids, lycopene and tomatoes and tomato products to modulate sirtuin 1 (SIRT1), a key metabolic sensor that directly links environmental nutrient signals to amelioration of inflammation in liver, intestine and adipose tissue as well as tumorigenesis secondary to diet-induced obesity. We addressed the causal effect of systemic SIRT1 activity on NAFLD development and the underlying mechanism involved in both liver and mesenteric adipose tissue (MAT). At 6 weeks of age, both SIRT1 homozygous male mice carrying a point mutation (H355Y, Sirt1Y/Y, n=10) that ablates the catalytic activity and their corresponding wild type littermates (WT, n=10) were fed a high fat diet (HFD, 60% calories from fat) for 34 weeks. Sirt1Y/Y mice showed significantly higher level of hepatic triglyceride, and a trend of more severe hepatic steatosis by histopathology. This steatosis was accompanied with higher levels of SREBP-1 and SCD1, the proteins involved in lipogenesis, and decreased phosphorylation of LKB1 and AMPK in the liver. Compared with wild-type mice, mRNA expression of lipogenic genes (lxrα, srebp-1c, scd1 and fas) in the mesenteric adipose tissue (MAT) increased significantly in Sirt1Y/Y mice. Fatty acid oxidation biomarkers (acox1, acox3, cpt, ucp1, sirt3) in both liver and MAT were comparable between groups. Interestingly, we observed that in Sirt1Y/Y mice, the mRNA level of hormone sensitive lipase (hsl), adipose triglyceride lipase (atgl) and perilipin-2 (plin-2), all involved in lipolysis, significantly increased in MAT, but not in epididymal adipose tissue. These changes positively correlated with circulating free fatty acid (FFA) concentrations and higher hepatic mRNA expression of cd36 for FFA uptake. The present study has provided novel evidence to suggest that under HFD-induced metabolic surplus, the lack of SIRT1 catalytic activity promotes release of FFA from MAT into systemic circulation and escalate NAFLD by interfering with lipid homeostasis in both liver and MAT.
Publications
- Type:
Journal Articles
Status:
Submitted
Year Published:
2017
Citation:
Cheng J, Liu C, Hu KQ, Greenberg A, Wu D, Ausman LM, McBurney MW and Wang X-D. Ablation of systemic SIRT1 activity promotes nonalcoholic fatty liver disease by affecting liver-mesenteric adipose tissue fatty acid mobilization. (Submitted)
- Type:
Journal Articles
Status:
Submitted
Year Published:
2017
Citation:
Li C, Liu C, Fu M, Aizawa K, Takahashi S, Hu KQ, von Lintig J, and Wang X-D. Dietary tomato powder supplementation alleviates high-fat diet induced hepatic steatosis and inflammatory response in beta-carotene-15, 15-oxygenase and beta-carotene-9, 10-oxygenase double knockout mice. (Submitted)
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Aizawa K, Liu C, Veeramachaneni S, Hu KQ, Smith DE, Wang X-D. Tobacco carcinogen (NNK) induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation. International Journal of Cancer, 139(5):1171-81, 2016
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Progress 02/15/15 to 02/14/16
Outputs
Target Audience:Consumers, in particular persons with elevated body mass indices, will benefit from potential health promoting effects of tomato and tomato products, and from increased knowledge of the various biological activities of lycopene and apolycopenoids. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?The project has provided an ideal training environment for Tufts PhD students. In particular, this project helped greatly students to understand how dietary components and molecular pathways can influence inflammation and cancer development. This project will assist individual with great potential to become a scientist in the field of nutrition and cancer prevention. How have the results been disseminated to communities of interest?We will report our finding in the coming AFRI project director meeting and 2016 Experimental Biology meeting. Our work will be highly significant for the dietary tomato prevention of obesity and obesity-related complications as well as other chronic diseases. What do you plan to do during the next reporting period to accomplish the goals?We are so excited on the preliminary results suggesting that the ablating SIRT1 activity may promote hepatic steatosis and liver tumor development by reducing adiponectin signaling in adipose tissue of mice. We will coduct additional study (e.g., increase sample size) to confirm our hypothesis. This animal model also set up a stage for our next projects to investigating protective effects of tomato/lycopenoid intervention using sirt1 mutation mouse model. We will focus on the understanding of common and distinct mechanisms involved by which tomatoes, as well as the actions of tomato components (e.g., apolycopenoids) against inflammation and liver cancer development.
Impacts
What was accomplished under these goals?
Accomplishment Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver diseases in the United States and its incidence has increased significantly in recent decades. It affects as much as 30 percent of the adult population and is strongly associated with obesity, diabetes, cardiovascular disease, and cancer development. Given the epidemic of obesity, poor prognosis and a high mortality rate of obesity-related liver cancer, prevention of NAFLD development, especially by dietary means, represents an important disease control strategy. Beneficial effects of tomatoes and tomato products on cancer risk have been found in many epidemiological studies, with strong evidence implicating lycopene as a micronutrient with important health benefits.Lycopene can be converted by two enzymes (beta-carotene-15, 15'-oxygenase (BCO1) and beta-carotene-9', 10'-oxygenase (BCO2)) into biological active compounds (called apo-lycopenoids). In the study supported by AFRI, research scientists from Tufts University provided strong evidence demonstrating that tomato powder (as whole tomato) supplementation is protective against high fat diet-induced NAFLD and the development of liver cancer in the absence of BCO1/BCO2 enzymes in mouse models. The potential mechanism underlying the anti-NAFLD/liver cancer efficacy manifested by tomato powder, possible due to a combined or synergistic effect of multiple constituents in tomatoes (e.g., vitamin E, vitamin C, phytoene and phytofluene). This data led to a great interesting for the nutrition and cancer prevention field to study whether and how tomato powder as whole food prevent high fat diet/obesity related insulin resistance, oxidative stress, inflammation and cancers. Objectives: Objective 1) To investigate the biological function of apocarotenoids from tomatoes and tomato products or from enzymatic cleavage of lycopene by mammalian carotenoid oxygenases as important protective agents against the high fat diet-induced inflammation and tumorigenesis We examined whether or not the whole tomato (tomato powder, TP) can inhibit high fat diet (HFD)-induced hepatic steatosis, inflammation and HCC in the absence of both BCO1/BCO2 in mice. BCO1/BCO2 double KO mice were injected with a carcinogen (diethylnitrosamine, DEN, i.p. 25 mg/kg body weight) at 2 weeks of age. At the age of 6 weeks, the mice were randomly assigned to either the HFD (n=9, 60% of energy as fat) feeding alone group or the HFD feeding with TP supplementation (n=9, HFD+TP, 41.8 g TP/kg diet, equivalent to 36 mg lycopene/day in human, which is 3-4 times higher than the average intake of lycopene) for 24 weeks. BCO1/BCO2 double KO mice (n=9) of the same age were fed with a chow diet as the control group. Results showed that TP supplementation significantly decreased hepatic steatosis and HCC development (67% reduction in incidence, 83% reduction in multiplicity, and 95% reduction in tumor volume) in BCO1/BCO2 double KO mice, as compared with the mice fed with HFD alone. The protective effects of TP supplementation were associated with 1) decreased hepatic inflammatory foci (89% reduction) and mRNA expressions of pro-inflammatory biomarkers [interleukin (IL)-6, IL-12a, monocyte chemoattractant protein-1, and inducible NO synthase]; 2) increased mRNA expressions of deacetylase sirtuin 1, sirtuin 3, and nicotinamide phosphoribosyltransferase involving NAD+ production; and 3) restored HFD-reduced circadian clock gene expressions (circadian locomotor output cycles kaput, period 2, and cryptochrome-2) to the normal levels of the control group. Taken together, the present study demonstrates that dietary TP can effectively inhibit HFD-promoted steatosis, inflammation and tumorigenesis in the absence of BCO1/BCO2. The protective effects of TP against HFD-induced liver injury may involve the regulations of sirtuin deacetylation and its related molecular clock function. Objective 2) To determine the ability of apocarotenoids, lycopene and tomatoes and tomato products to modulate sirtuin 1 (SIRT1), a key metabolic sensor that directly links environmental nutrient signals to amelioration of inflammation in liver, intestine and adipose tissue as well as tumorigenesis secondary to diet-induced obesity. We investigated whether the lacking SIRT1 activity can increase susceptibility to developing hepatic steatosis and hepatocellular carcinoma and its potential mechanisms involved in mice. Both sirt1y/y homozygous mice (n=14) carrying a point mutation (H355Y, 129/SvJ) that ablates the catalytic activity and their corresponding wild type littermates sirt1+/+ mice (n=18) were injected with diethylnitrosamine (DEN, 25 mg/kg body weight i.p.) at 2 weeks of age. At 6 weeks of age, all of mice were fed with high fat diet (HFD, 60% calories from fat; Bioserv) for additional 34 weeks. Results showed that, as compared to sirt1+/+ mice, SIRT1 activity ablation resulted a trend of increased hepatic steatosis (pathological grading median: 2 vs. 3) and liver tumor incidence (positive 50% vs 64.3%) without altering body weight and liver weight. The lesions was accompanied with increased mRNA expressions of lipid uptake-related gene (CD36 and htgl) and significant decreased ACC phosphorylation, PPARα and PPARα-regulated microsomal transfer protein (MTP), in the livers of sirt1y/y mice. Interestingly, mRNA expressions of adiponectin, pgc1α and pparg in mesenteric adipose tissue were also significantly lower in sirt1y/y mice than that of sirt1+/+ mice, indicating biologic action of sirt1 on both liver and adipose tissue. Although we need additional sample size for this investigation, the preliminary results suggest that the ablating SIRT1 activity may promote hepatic steatosis and liver tumor development by reducing adiponectin signaling in adipose tissue of mice. This animal model also set up a stage for our next projects to investigating protective effects of tomato/lycopenoid intervention.
Publications
- Type:
Conference Papers and Presentations
Status:
Submitted
Year Published:
2016
Citation:
Abstract submitted
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