TY - JOUR
T1 - Eicosapentaenoic acid improves hepatic metabolism and reduces inflammation independent of obesity in high-fat-fed mice and in HepG2 cells
AU - Albracht-Schulte, Kembra
AU - Gonzalez, Samantha
AU - Jackson, Abigail
AU - Wilson, Savanna
AU - Ramalingam, Latha
AU - Kalupahana, Nishan S.
AU - Moustaid-Moussa, Naima
N1 - Funding Information:
This research was supported by startup funds from Texas Tech University (College of Human Sciences,Office of the Vice President for Research and The Obesity Research Cluster). Initial support for the animal studies was provided by a predoctoral Fellowship from AHA (N.S.K.) and a USDA NIFA NRI award (N.M.M.). NMM is in part supported by the National Institutes of Health National Center for Complementary and Integrative Health (NIH NCCIH) award number 1 R15 AT008879-01A1. KAS is a United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) Fellow, supported by the Food, Agriculture, Natural Resources, and Human Sciences Education and Literacy Initiative (ELI) Predoctoral Fellowship of the Agriculture and Food Research Initiative (AFRI) under award number 2017-67011-26029.
Funding Information:
Funding: This research was supported by startup funds from Texas Tech University (College of in part supported by the National Institutes of Health National Center for Complementary and Integrative Health (NIH HumanNCCIH) Scieawarnces,d numberOffice1of R15thAeTV0i0ce887Pres9-01identA1. KASfor isReaseUnitedarch anStatesd The DepartmentObesity Reseof Agriculturarch Clustee(USDA)r). Initial support for the animal studies was provided by a predoctoral Fellowship from AHA (N.S.K.) and Haunmda na SUciSeDncAeNs EIFduAcNatRioIn aawndarLdit e(rNa.Mcy.MIn.i)t.i aNtiMveM(EiLsIi)nP preadrot cstuorpaploFretelldow bsyh itphoeNf tahteioAnaglr iIcnuslttiutureteasn dof Food Health National Center for Complementary and Integrative Health (NIH NCCIH) award number 1 R15 AT008879-01A1. KAS is a United States Department of Agriculture (USDA) National Institute of wouldFaolosod lainkedtAo garcikcnuoltwurleed(gNeIFKAaz) FSuelrloowwi,escufpopr hoirsteads sbisytathncee Fwoiothd,t hAgerfiactutyltaucride, Nanaatulyrsaels .Resources, and
Funding Information:
Author Contributions: N.S.K. and N.M.-M. designed the initial animal study; K.A.-S. conducted majority of the data with input from N.M.-M., L.R., and N.S.K. K.A.-S. wrote the initial draft, which was modified most of the research with assistance from L.R. as well as S.G., A.J., and S.W. for the in vitro studies; approKve.Ad .t-hS.e afinnaallymzeadn uthscer impat.jority of the data with input from N.M.-M., L.R., and N.S.K. K.A.-S wrote the initial draft, which was modified after feedback from all coauthors; and N.M.-M. has primary Funding: This research was supported by startup funds from Texas Tech University (College of Human Sciences, Officeresponsiof the VibcieliPrty fesidentor content. for ResearAll authors ch andreThead and approObesity Researved chthe Cluster).final manuscInitialript. support for the animal studies
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/3
Y1 - 2019/3
N2 - The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide, concurrent with increased obesity. Thus, there is urgent need for research that can lead to effective NAFLD prevention/treatment strategies. Omega-3 polyunsaturated fatty acids (n-3 PUFAs), including eicosapentaenoic acid (EPA), improve inflammation-and dyslipidemia-related metabolic disorders; however, mechanisms mediating the benefits of n-3 PUFAs in NAFLD treatment are less understood. We previously reported that EPA reversed obesity-induced hepatic steatosis in high-fat (HF)-fed B6 mice. Utilizing a combination of biochemical analyses of liver tissues from HF and HF-EPA-fed mice and a series of in vitro studies in tumor necrosis factor-alpha (TNF-α)-stimulated HepG2 cells, we dissect the mechanistic effects of EPA in reducing hepatic steatosis, including the role of EPA-targeted microRNAs (miRNA). With EPA, hepatic lipid metabolism was improved in HF-EPA mice, as indicated by decreased protein and messenger RNA (mRNA) levels of fatty acid synthase (FASN) and acetyl-CoA carboxylase (Acaca) gene, and increased mRNA levels for the peroxisome proliferator activated receptor-α (Pparα), and carnitine palmitoyltransferase (Cpt) 1a and 2 genes in the HF-EPA mice. Additionally, inflammation was reduced, as shown by decreased tumor necrosis factor-alpha (Tnfα) gene expression. Accordingly, EPA also significantly reduced FASN and ACACA mRNAs in human HepG2 cells. Glycolysis, estimated by extracellular acidification rate, was significantly reduced in HepG2 cells treated with EPA vs. vehicle. Furthermore, we identified several miRNAs that are regulated by EPA in mouse liver, including miR-19b-3p, miR-21a-5p, and others, which target lipid metabolism and inflammatory pathways. In conclusion, our findings provide novel mechanistic evidence for beneficial effects of EPA in NAFLD, through the identification of specific genes and miRNAs, which may be further exploited as future NAFLD therapies.
AB - The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide, concurrent with increased obesity. Thus, there is urgent need for research that can lead to effective NAFLD prevention/treatment strategies. Omega-3 polyunsaturated fatty acids (n-3 PUFAs), including eicosapentaenoic acid (EPA), improve inflammation-and dyslipidemia-related metabolic disorders; however, mechanisms mediating the benefits of n-3 PUFAs in NAFLD treatment are less understood. We previously reported that EPA reversed obesity-induced hepatic steatosis in high-fat (HF)-fed B6 mice. Utilizing a combination of biochemical analyses of liver tissues from HF and HF-EPA-fed mice and a series of in vitro studies in tumor necrosis factor-alpha (TNF-α)-stimulated HepG2 cells, we dissect the mechanistic effects of EPA in reducing hepatic steatosis, including the role of EPA-targeted microRNAs (miRNA). With EPA, hepatic lipid metabolism was improved in HF-EPA mice, as indicated by decreased protein and messenger RNA (mRNA) levels of fatty acid synthase (FASN) and acetyl-CoA carboxylase (Acaca) gene, and increased mRNA levels for the peroxisome proliferator activated receptor-α (Pparα), and carnitine palmitoyltransferase (Cpt) 1a and 2 genes in the HF-EPA mice. Additionally, inflammation was reduced, as shown by decreased tumor necrosis factor-alpha (Tnfα) gene expression. Accordingly, EPA also significantly reduced FASN and ACACA mRNAs in human HepG2 cells. Glycolysis, estimated by extracellular acidification rate, was significantly reduced in HepG2 cells treated with EPA vs. vehicle. Furthermore, we identified several miRNAs that are regulated by EPA in mouse liver, including miR-19b-3p, miR-21a-5p, and others, which target lipid metabolism and inflammatory pathways. In conclusion, our findings provide novel mechanistic evidence for beneficial effects of EPA in NAFLD, through the identification of specific genes and miRNAs, which may be further exploited as future NAFLD therapies.
KW - Eicosapentaenoic acid
KW - Inflammation
KW - Nonalcoholic fatty liver disease
KW - Obesity
KW - Omega-3 polyunsaturated fatty acids
UR - http://www.scopus.com/inward/record.url?scp=85062978158&partnerID=8YFLogxK
U2 - 10.3390/nu11030599
DO - 10.3390/nu11030599
M3 - Article
C2 - 30871035
AN - SCOPUS:85062978158
VL - 11
JO - Nutrients
JF - Nutrients
SN - 2072-6643
IS - 3
M1 - 599
ER -