Transcriptional Regulation of Human and Rat Hepatic Lipid Metabolism by the Grapefruit Flavonoid Naringenin: Role of PPARα, PPARγ and LXRα
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{"title"=>"Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: Role of PPARα, PPARγ and LXRα", "type"=>"journal", "authors"=>[{"first_name"=>"Jonathan", "last_name"=>"Goldwasser", "scopus_author_id"=>"24512248800"}, {"first_name"=>"Pazit Y.", "last_name"=>"Cohen", "scopus_author_id"=>"7402924038"}, {"first_name"=>"Eric", "last_name"=>"Yang", "scopus_author_id"=>"36639059600"}, {"first_name"=>"Patrick", "last_name"=>"Balaguer", "scopus_author_id"=>"7003608368"}, {"first_name"=>"Martin L.", "last_name"=>"Yarmush", "scopus_author_id"=>"7102874023"}, {"first_name"=>"Yaakov", "last_name"=>"Nahmias", "scopus_author_id"=>"12752628500"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"20811644", "scopus"=>"2-s2.0-77957871769", "doi"=>"10.1371/journal.pone.0012399", "sgr"=>"77957871769", "pui"=>"359754310"}, "id"=>"59fed097-ac0b-3b4d-80d0-1e3b928f1a6e", "abstract"=>"Disruption of lipid and carbohydrate homeostasis is an important factor in the development of prevalent metabolic diseases such as diabetes, obesity, and atherosclerosis. Therefore, small molecules that could reduce insulin dependence and regulate dyslipidemia could have a dramatic effect on public health. The grapefruit flavonoid naringenin has been shown to normalize lipids in diabetes and hypercholesterolemia, as well as inhibit the production of HCV. Here, we demonstrate that naringenin regulates the activity of nuclear receptors PPARα, PPARγ, and LXRα. We show it activates the ligand-binding domain of both PPARα and PPARγ, while inhibiting LXRα in GAL4-fusion reporters. Using TR-FRET, we show that naringenin is a partial agonist of LXRα, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPARα co-activator, PGC1α. The flavonoid activates PPAR response element (PPRE) while suppressing LXRα response element (LXRE) in human hepatocytes, translating into the induction of PPAR-regulated fatty acid oxidation genes such as CYP4A11, ACOX, UCP1 and ApoAI, and inhibition of LXRα-regulated lipogenesis genes, such as FAS, ABCA1, ABCG1, and HMGR. This effect results in the induction of a fasted-like state in primary rat hepatocytes in which fatty acid oxidation increases, while cholesterol and bile acid production decreases. Our findings explain the myriad effects of naringenin and support its continued clinical development. Of note, this is the first description of a non-toxic, naturally occurring LXRα inhibitor.", "link"=>"http://www.mendeley.com/research/transcriptional-regulation-human-rat-hepatic-lipid-metabolism-grapefruit-flavonoid-naringenin-role-p-2", "reader_count"=>62, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>14, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>4, "Student > Master"=>8, "Other"=>4, "Student > Bachelor"=>9, "Lecturer"=>3, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>14, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>4, "Student > Master"=>8, "Other"=>4, "Student > Bachelor"=>9, "Lecturer"=>3, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Engineering"=>1, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>9, "Nursing and Health Professions"=>1, "Agricultural and Biological Sciences"=>31, "Medicine and Dentistry"=>9, "Arts and Humanities"=>1, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Psychology"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>31}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>9}, "Unspecified"=>{"Unspecified"=>4}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "China"=>1, "Japan"=>1, "United Kingdom"=>1, "Italy"=>1, "Portugal"=>1}, "group_count"=>3}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/834100"], "description"=>"<p>(a) Naringenin dose-dependently enhanced PPRE activity, in Huh7 cells transiently transfected with a PPRE reporter, reaching 17%±7% (p<0.05) at 200 µM. Induction was not different from PPAR agonists WY14,643 and ciglitazone. (b) Naringenin induced the expression of PPARα coactivator PGC1α by 14-fold (p = 0.001) as well as PPARα-regulated fatty acid oxidation genes CYP4A11/22, ACOX, UCP1 and ApoAI. Huh7 cells were treated with naringenin for 24 hours and mRNA isolated and anlysed by qRT-PCR. (c) Naringenin dose-dependently suppressed LXRE activity, in Huh7 cells transiently transfected with a LXRE reporter, reaching a 50.3%±2.6% (p<0.001) inhibition at 150 µM. (d) Naringenin inhibited the expression of LXRα-regulated lipogenesis genes ABCA1, ABCG1, HMGR, and FASN. Cell viability under all conidtions was greater than 95%.</p>", "links"=>[], "tags"=>["activates", "ppre-driven", "inhibits", "lxre-driven"], "article_id"=>504465, "categories"=>["Molecular Biology", "Neuroscience", "Biotechnology", "Virology", "Pharmacology", "Cell Biology"], "users"=>["Jonathan Goldwasser", "Pazit Y. Cohen", "Eric Yang", "Patrick Balaguer", "Martin L. Yarmush", "Yaakov Nahmias"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012399.g003", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Naringenin_activates_PPRE_driven_and_inhibits_LXRE_driven_gene_expression_in_human_hepatocytes_/504465", "title"=>"Naringenin activates PPRE-driven and inhibits LXRE-driven gene expression in human hepatocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-25 01:14:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/415211"], "description"=>"<div><p>Disruption of lipid and carbohydrate homeostasis is an important factor in the development of prevalent metabolic diseases such as diabetes, obesity, and atherosclerosis. Therefore, small molecules that could reduce insulin dependence and regulate dyslipidemia could have a dramatic effect on public health. The grapefruit flavonoid naringenin has been shown to normalize lipids in diabetes and hypercholesterolemia, as well as inhibit the production of HCV. Here, we demonstrate that naringenin regulates the activity of nuclear receptors PPARα, PPARγ, and LXRα. We show it activates the ligand-binding domain of both PPARα and PPARγ, while inhibiting LXRα in GAL4-fusion reporters. Using TR-FRET, we show that naringenin is a partial agonist of LXRα, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPARα co-activator, PGC1α. The flavonoid activates PPAR response element (PPRE) while suppressing LXRα response element (LXRE) in human hepatocytes, translating into the induction of PPAR-regulated fatty acid oxidation genes such as CYP4A11, ACOX, UCP1 and ApoAI, and inhibition of LXRα-regulated lipogenesis genes, such as FAS, ABCA1, ABCG1, and HMGR. This effect results in the induction of a <em>fasted</em>-like state in primary rat hepatocytes in which fatty acid oxidation increases, while cholesterol and bile acid production decreases. Our findings explain the myriad effects of naringenin and support its continued clinical development. Of note, this is the first description of a non-toxic, naturally occurring LXRα inhibitor.</p></div>", "links"=>[], "tags"=>["transcriptional", "hepatic", "lipid", "metabolism", "grapefruit", "flavonoid"], "article_id"=>141987, "categories"=>["Molecular Biology", "Neuroscience", "Biotechnology", "Cancer", "Pharmacology", "Cell Biology"], "users"=>["Jonathan Goldwasser", "Pazit Y. Cohen", "Eric Yang", "Patrick Balaguer", "Martin L. Yarmush", "Yaakov Nahmias"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012399", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Transcriptional_Regulation_of_Human_and_Rat_Hepatic_Lipid_Metabolism_by_the_Grapefruit_Flavonoid_Naringenin_Role_of_PPAR_PPAR_and_LXR_/141987", "title"=>"Transcriptional Regulation of Human and Rat Hepatic Lipid Metabolism by the Grapefruit Flavonoid Naringenin: Role of PPARα, PPARγ and LXRα", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-25 00:33:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/834230"], "description"=>"<p>Real-Time qRT-PCR Primers.</p>", "links"=>[], "tags"=>["qrt-pcr"], "article_id"=>504596, "categories"=>["Molecular Biology", "Neuroscience", "Biotechnology", "Virology", "Pharmacology", "Cell Biology"], "users"=>["Jonathan Goldwasser", "Pazit Y. Cohen", "Eric Yang", "Patrick Balaguer", "Martin L. Yarmush", "Yaakov Nahmias"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012399.t001", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Real_Time_qRT_PCR_Primers_/504596", "title"=>"Real-Time qRT-PCR Primers.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-08-25 01:16:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/834167"], "description"=>"<p>(a) Huh7 cells were stimulated for 24 hours with 200 µM naringenin, 10 µM WY14,643, or 10 µM ciglitazone. Naringenin treatment led to a 73%±9% (p<0.001) reduction in ApoB production, while WY14,643 led to a 33%±12% (p<0.01) reduction. Treatment with cigilitazone did not lead to a significant change in VLDL production. (b) Primary rat hepatocytes were stimulated with 200 µM naringenin or 10 µM WY14,643. Naringenin treatment led to a 61% (p<0.001) reduction in triglyceride production and 17% increase in ketone body formation, not different from WY14,643. However, naringenin treatment led to a 32%±11% (p = 0.005) reduction in bile salt production, while WY14,643 did not. Urea accumulation in the media did not change significantly. (c) Intracellular levels of triglycerides in primary rat hepatocytes stimulated with naringenin. A slight decrease is observed. (d) Naringenin effect on SRE-driven gene expression. We show that naringein induces LDLR transcription by 26% (p = 0.02) while inhibiting HMGCS transcription by 13% (p = 0.001). It is thought that each promoter is regulated by a different SREBP isoform.</p>", "links"=>[], "tags"=>["induced", "hepatic", "lipid"], "article_id"=>504535, "categories"=>["Molecular Biology", "Neuroscience", "Biotechnology", "Virology", "Pharmacology", "Cell Biology"], "users"=>["Jonathan Goldwasser", "Pazit Y. Cohen", "Eric Yang", "Patrick Balaguer", "Martin L. Yarmush", "Yaakov Nahmias"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012399.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Naringenin_induced_a_fasted_like_state_in_hepatic_lipid_metabolism_/504535", "title"=>"Naringenin induced a <i>fasted</i>-like state in hepatic lipid metabolism.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-25 01:15:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/833868"], "description"=>"<p>HG<sub>5</sub>LN reporter cells expressing GAL4-PPARα (a) and GAL4-PPARγ (b) reporters were treated with increasing concentrations of naringenin. Naringenin dose-dependently activated PPARα reaching 24%±0.2% induction at 240 µM (P<0.001); and activated PPARγ up to 57%±0.3% at 80 µM (P<0.005). Data is presented as percent activation relative to 1 µM of classical agonists GW7647 and BRL49653, respectively. (c) LanthaScreen TR-FRET assay, demonstrating that naringenin did not affect the binding of the PGC1α co-activator peptide to recombinant PPARα LBD. (d) In contrast, the classical PPARα agonist GW7647 induces a dose-dependent binding of PGC1α to PPARα in the same assay.</p>", "links"=>[], "tags"=>["induces", "activation", "ligand-binding"], "article_id"=>504234, "categories"=>["Molecular Biology", "Neuroscience", "Biotechnology", "Virology", "Pharmacology", "Cell Biology"], "users"=>["Jonathan Goldwasser", "Pazit Y. Cohen", "Eric Yang", "Patrick Balaguer", "Martin L. Yarmush", "Yaakov Nahmias"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012399.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Naringenin_induces_activation_of_PPAR_945_and_PPAR_947_ligand_binding_domains_/504234", "title"=>"Naringenin induces activation of PPARα and PPARγ ligand-binding domains.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-25 01:10:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/833962"], "description"=>"<p>(a) LXR-alpha-UAS-bla HEK 293T cells were stimulated with 4.7 nM TO901317 and exposed to increasing concentrations of naringenin. Naringenin dose-dependently inhibited LXRα activity, reaching 28.4%±0.4% (p<0.01) and 39.1%±9.4% (p<0.05) at concentrations of 126 µM and 400 µM, respectively. (b-d) Lanthascreen TR-FRET assay, demonstrating that naringenin weakly increased the binding of Trap 220/Drip-2 co-activator peptide to recombinant LXRα LBD, and inhibited this binding in the presence of TO901317, LXRα classical agonist. (b) Naringenin is a weak agonist, enhancing the binding of the LXRα LBD to the Trap 220/Drip-2 co-activator moderately, yet significantly, in a dose-dependent manner reaching 38.0%±2.8% activation. (c) LXRα agonist TO901317 strongly enhanced co-activator binding. (d) When treated with 250 nM TO901317, increasing concentrations of naringenin led to an inhibition of the TR-FRET signal, reaching 15.0%±4.1% inhibition (p<0.01) at 133 µM.</p>", "links"=>[], "tags"=>["agonist", "ligand-binding"], "article_id"=>504332, "categories"=>["Molecular Biology", "Neuroscience", "Biotechnology", "Virology", "Pharmacology", "Cell Biology"], "users"=>["Jonathan Goldwasser", "Pazit Y. Cohen", "Eric Yang", "Patrick Balaguer", "Martin L. Yarmush", "Yaakov Nahmias"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012399.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Naringenin_is_a_partial_agonist_of_LXR_945_ligand_binding_domain_/504332", "title"=>"Naringenin is a partial agonist of LXRα ligand-binding domain.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-25 01:12:12"}

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