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Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice.
Metabolism. 2013 Nov; 62(11):1651-61.M

Abstract

OBJECTIVE

This study investigated the effects of dietary methionine restriction (MR) on the progression of established hepatic steatosis in the leptin-deficient ob/ob mouse.

MATERIAL/METHODS

Ten-week-old ob/ob mice were fed diets containing 0.86% (control-fed; CF) or 0.12% methionine (MR) for 14 weeks. At 14 weeks, liver and fat were excised and blood was collected for analysis. In another study, blood was collected to determine in vivo triglyceride (TG) and very-low-density lipoprotein (VLDL) secretion rates. Liver histology was conducted to determine the severity of steatosis. Hepatic TG, free fatty acid levels, and fatty acid oxidation (FAO) were also measured. Gene expression was analyzed by quantitative PCR.

RESULTS

MR reversed the severity of steatosis in the ob/ob mouse. This was accompanied by reduced body weight despite similar weight-specific food intake. Compared with the CF group, hepatic TG levels were significantly reduced in response to MR, but adipose tissue weight was not decreased. MR reduced insulin and HOMA ratios but increased total and high-molecular-weight adiponectin levels. Scd1 gene expression was significantly downregulated, while Acadvl, Hadha, and Hadhb were upregulated in MR, corresponding with increased β-hydroxybutyrate levels and a trend toward increased FAO. The VLDL secretion rate was also significantly increased in the MR mice, as were the mRNA levels of ApoB and Mttp. The expression of inflammatory markers, such as Tnf-α and Ccr2, was also downregulated by MR.

CONCLUSIONS

Our data indicate that MR reverses steatosis in the ob/ob mouse liver by promoting FAO, increasing the export of lipids, and reducing obesity-related inflammatory responses.

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Authors+Show Affiliations

Malloy VL
Orentreich Foundation for the Advancement of Science, Inc., 855 Route 301, Cold Spring-on-Hudson, NY 10516, USA. Electronic address: vmalloy@orentreich.org.
Perrone CE
No affiliation info available
Mattocks DA
No affiliation info available
Ables GP
No affiliation info available
Caliendo NS
No affiliation info available
Orentreich DS
No affiliation info available
Orentreich N
No affiliation info available

MeSH

3-Hydroxybutyric AcidAnimalsBiomarkersBlood GlucoseDietDisease ProgressionFatty AcidsFatty LiverGene Expression RegulationHomeostasisInflammationInsulinLeptinLipid MetabolismLipoproteins, VLDLLiverMaleMethionineMiceMice, ObeseObesityOxidation-ReductionSeverity of Illness IndexTriglycerides

Pub Type(s)

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

Language

eng

PubMed ID

23928105

Citation

Malloy, Virginia L., et al. "Methionine Restriction Prevents the Progression of Hepatic Steatosis in Leptin-deficient Obese Mice." Metabolism: Clinical and Experimental, vol. 62, no. 11, 2013, pp. 1651-61.
Malloy VL, Perrone CE, Mattocks DA, et al. Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice. Metabolism. 2013;62(11):1651-61.
Malloy, V. L., Perrone, C. E., Mattocks, D. A., Ables, G. P., Caliendo, N. S., Orentreich, D. S., & Orentreich, N. (2013). Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice. Metabolism: Clinical and Experimental, 62(11), 1651-61. https://doi.org/10.1016/j.metabol.2013.06.012
Malloy VL, et al. Methionine Restriction Prevents the Progression of Hepatic Steatosis in Leptin-deficient Obese Mice. Metabolism. 2013;62(11):1651-61. PubMed PMID: 23928105.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice. AU - Malloy,Virginia L, AU - Perrone,Carmen E, AU - Mattocks,Dwight A L, AU - Ables,Gene P, AU - Caliendo,Nicholas S, AU - Orentreich,David S, AU - Orentreich,Norman, Y1 - 2013/08/05/ PY - 2013/02/28/received PY - 2013/05/30/revised PY - 2013/06/27/accepted PY - 2013/8/10/entrez PY - 2013/8/10/pubmed PY - 2014/1/7/medline KW - ALT KW - AST KW - Acac KW - Acadvl KW - Adiponectin KW - ApoB KW - C-C chemokine receptor-2 KW - CF KW - Ccr2 KW - Cd 36 KW - Chrebp KW - Cpt1a KW - Dgat KW - EGF-like module-containing mucin-like hormone receptor-like 1 KW - Emr1 KW - FAO KW - FFA KW - Fasn KW - Fatty acid oxidation KW - Fatty liver KW - GSH KW - Gpam KW - HDL KW - HFD KW - HMW KW - HOMA KW - Hadha and Hadhb KW - IL6 KW - IR KW - Inflammation KW - Itgax KW - LDL KW - Lxr KW - MR KW - Mttp KW - NAFLD KW - NASH KW - Pklr KW - Pnpla2 KW - Pnpla3 KW - Pparα KW - Pparγ KW - ROS KW - Scd1 KW - Srebf1 KW - TG KW - TNF-α KW - Triglyceride KW - VLDL KW - acetyl-CoA carboxylase KW - acyl-coenzyme A dehydrogenase, very long chain KW - alanine aminotransferase KW - apolipoprotein B KW - aspartate aminotransferase KW - carbohydrate regulatory binding protein KW - carnitine palmitoyltransferase-1a KW - control-fed KW - diacylglycerol O-acyltransferase KW - fatty acid oxidation KW - fatty acid synthase KW - free fatty acids KW - glutathione KW - hepatic CD36 antigen KW - high-density lipoprotein KW - high-fat diet KW - high-molecular-weight KW - homeostasis model assessment KW - hydroxyacyl-coenzyme A dehydrogenase/3-ketoacyl-coenzyme A thiolase/enoyl-coenzyme A hydratase (trifunctional protein), alpha and beta subunits, respectively KW - insulin resistance KW - integrin alpha X KW - interleukin-6 KW - liver X-receptor KW - low-density lipoprotein KW - methionine restriction KW - microsomal triglyceride transfer protein KW - mitochondrial glycerol-3-phosphate acyltransferase KW - non-alcoholic fatty liver disease KW - non-alcoholic steatohepatitis KW - ob/ob KW - obese mouse KW - patatin-like phospholipase domain containing 2 KW - patatin-like phospholipase domain containing 3 KW - peroxisome proliferator-activated receptor α KW - peroxisome proliferator-activated receptor γ KW - pyruvate kinase-liver and red blood cell KW - reactive oxygen species KW - stearoyl-coenzyme A desaturase-1 KW - sterol regulatory element binding transcription factor 1 KW - triglycerides KW - tumor necrosis factor-α KW - very-low-density lipoprotein SP - 1651 EP - 61 JF - Metabolism: clinical and experimental JO - Metabolism VL - 62 IS - 11 N2 - OBJECTIVE: This study investigated the effects of dietary methionine restriction (MR) on the progression of established hepatic steatosis in the leptin-deficient ob/ob mouse. MATERIAL/METHODS: Ten-week-old ob/ob mice were fed diets containing 0.86% (control-fed; CF) or 0.12% methionine (MR) for 14 weeks. At 14 weeks, liver and fat were excised and blood was collected for analysis. In another study, blood was collected to determine in vivo triglyceride (TG) and very-low-density lipoprotein (VLDL) secretion rates. Liver histology was conducted to determine the severity of steatosis. Hepatic TG, free fatty acid levels, and fatty acid oxidation (FAO) were also measured. Gene expression was analyzed by quantitative PCR. RESULTS: MR reversed the severity of steatosis in the ob/ob mouse. This was accompanied by reduced body weight despite similar weight-specific food intake. Compared with the CF group, hepatic TG levels were significantly reduced in response to MR, but adipose tissue weight was not decreased. MR reduced insulin and HOMA ratios but increased total and high-molecular-weight adiponectin levels. Scd1 gene expression was significantly downregulated, while Acadvl, Hadha, and Hadhb were upregulated in MR, corresponding with increased β-hydroxybutyrate levels and a trend toward increased FAO. The VLDL secretion rate was also significantly increased in the MR mice, as were the mRNA levels of ApoB and Mttp. The expression of inflammatory markers, such as Tnf-α and Ccr2, was also downregulated by MR. CONCLUSIONS: Our data indicate that MR reverses steatosis in the ob/ob mouse liver by promoting FAO, increasing the export of lipids, and reducing obesity-related inflammatory responses. SN - 1532-8600 UR - https://www.unboundmedicine.com/medline/citation/23928105/Methionine_restriction_prevents_the_progression_of_hepatic_steatosis_in_leptin_deficient_obese_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0026-0495(13)00193-5 DB - PRIME DP - Unbound Medicine ER -