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Comparative effects of the renin-angiotensin system blockers on nonalcoholic fatty liver disease and insulin resistance in C57BL/6 mice.
Metab Syndr Relat Disord 2014; 12(4):191-201MS

Abstract

BACKGROUND

The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. The current study evaluated the effects of RAS blockers in a model of diet-induced insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD).

METHODS

Male C57BL/6 mice were fed a standard chow (SC; 10% lipids, n=15) diet or a high-fat (HF; 50% lipids, n=60) diet for 8 weeks and then treated with aliskiren (HF-A; 50 mg/kg per day, n=15), enalapril (HF-E; 30 mg/kg per day, n=15), or losartan (HF-L; 10 mg/kg per day, n=15) for an additional 6 weeks. We assessed glucose and lipid metabolism, hepatic histopathology, the expression profile of genes and proteins affecting hepatic gluconeogenesis, RAS and insulin signaling, and lipid beta-oxidation and accumulation. The differences between the groups were tested via analysis of variance (ANOVA) and the post hoc Holm-Sidak test.

RESULTS

All treatments restored the up-regulation of hepatic RAS. The enalapril treatment, but not aliskiren or losartan, was effective in improving leptin, glucose intolerance, IR, hepatic steatosis, and triglycerides and in preventing increased hepatic protein levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and glucose transporter-2 (GLUT-2). Furthermore, enalapril improved the response to the deleterious effects of the HF diet by upregulating signal transduction through the insulin receptor substrate (IRS) 1/protein kinase B (Akt) pathway, as well as downregulating the protein levels and mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1c (SREBP-1c), and fatty acid synthase (FAS).

CONCLUSIONS

Enalapril was the most successful treatment in protecting against hepatic IR and NAFLD by enhancing hepatic insulin action, leptin, and gluconeogenesis and by reducing the lipogenic pathway and lipid accumulation in the liver.

Authors+Show Affiliations

Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro , Rio de Janeiro, Brazil .No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24517411

Citation

Frantz, Eliete Dalla Corte, et al. "Comparative Effects of the Renin-angiotensin System Blockers On Nonalcoholic Fatty Liver Disease and Insulin Resistance in C57BL/6 Mice." Metabolic Syndrome and Related Disorders, vol. 12, no. 4, 2014, pp. 191-201.
Frantz ED, Penna-de-Carvalho A, Batista Tde M, et al. Comparative effects of the renin-angiotensin system blockers on nonalcoholic fatty liver disease and insulin resistance in C57BL/6 mice. Metab Syndr Relat Disord. 2014;12(4):191-201.
Frantz, E. D., Penna-de-Carvalho, A., Batista, T. d. e. . M., Aguila, M. B., & Mandarim-de-Lacerda, C. A. (2014). Comparative effects of the renin-angiotensin system blockers on nonalcoholic fatty liver disease and insulin resistance in C57BL/6 mice. Metabolic Syndrome and Related Disorders, 12(4), pp. 191-201. doi:10.1089/met.2013.0129.
Frantz ED, et al. Comparative Effects of the Renin-angiotensin System Blockers On Nonalcoholic Fatty Liver Disease and Insulin Resistance in C57BL/6 Mice. Metab Syndr Relat Disord. 2014;12(4):191-201. PubMed PMID: 24517411.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparative effects of the renin-angiotensin system blockers on nonalcoholic fatty liver disease and insulin resistance in C57BL/6 mice. AU - Frantz,Eliete Dalla Corte, AU - Penna-de-Carvalho,Aline, AU - Batista,Thais de Medeiros, AU - Aguila,Marcia Barbosa, AU - Mandarim-de-Lacerda,Carlos Alberto, Y1 - 2014/02/11/ PY - 2014/2/13/entrez PY - 2014/2/13/pubmed PY - 2014/12/15/medline SP - 191 EP - 201 JF - Metabolic syndrome and related disorders JO - Metab Syndr Relat Disord VL - 12 IS - 4 N2 - BACKGROUND: The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. The current study evaluated the effects of RAS blockers in a model of diet-induced insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). METHODS: Male C57BL/6 mice were fed a standard chow (SC; 10% lipids, n=15) diet or a high-fat (HF; 50% lipids, n=60) diet for 8 weeks and then treated with aliskiren (HF-A; 50 mg/kg per day, n=15), enalapril (HF-E; 30 mg/kg per day, n=15), or losartan (HF-L; 10 mg/kg per day, n=15) for an additional 6 weeks. We assessed glucose and lipid metabolism, hepatic histopathology, the expression profile of genes and proteins affecting hepatic gluconeogenesis, RAS and insulin signaling, and lipid beta-oxidation and accumulation. The differences between the groups were tested via analysis of variance (ANOVA) and the post hoc Holm-Sidak test. RESULTS: All treatments restored the up-regulation of hepatic RAS. The enalapril treatment, but not aliskiren or losartan, was effective in improving leptin, glucose intolerance, IR, hepatic steatosis, and triglycerides and in preventing increased hepatic protein levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and glucose transporter-2 (GLUT-2). Furthermore, enalapril improved the response to the deleterious effects of the HF diet by upregulating signal transduction through the insulin receptor substrate (IRS) 1/protein kinase B (Akt) pathway, as well as downregulating the protein levels and mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1c (SREBP-1c), and fatty acid synthase (FAS). CONCLUSIONS: Enalapril was the most successful treatment in protecting against hepatic IR and NAFLD by enhancing hepatic insulin action, leptin, and gluconeogenesis and by reducing the lipogenic pathway and lipid accumulation in the liver. SN - 1557-8518 UR - https://www.unboundmedicine.com/medline/citation/24517411/Comparative_effects_of_the_renin_angiotensin_system_blockers_on_nonalcoholic_fatty_liver_disease_and_insulin_resistance_in_C57BL/6_mice_ L2 - https://www.liebertpub.com/doi/full/10.1089/met.2013.0129?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -