Hepatic protein expression of lean mice and obese diabetic mice treated with peroxisome proliferator‐activated receptor activators

Abstract

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that modulate lipid and glucose homeostasis. In the clinic, PPARalpha and PPARgamma agonists are used to treat hypertriglyceridemia and insulin resistance of diabetes, respectively. To gain further insight into the molecular mechanisms underlying the therapeutic actions of these drugs, we have by two-dimensional electrophoresis and mass spectrometry performed a comparative analysis of the hepatic protein expression profiles of lean and obese (ob/ob) mice, and obese mice treated with WY14643 (PPARalpha agonist) or rosiglitazone (PPARgamma agonist). We found that livers from obese mice displayed higher levels of enzymes involved in fatty acid oxidation and lipogenesis compared to lean mice and these differences were further amplified by treatment with both PPAR activators. WY14643 normalized the expression levels of several enzymes involved in glycolysis, gluconeogenesis and amino acid metabolism in the obese mice to the levels of lean mice, whereas rosiglitazone partially normalized levels of enzymes involved in amino acid metabolism. In summary, a classical proteomics approach was successfully used to characterize differences at the hepatic proteome level between lean and obese diabetic mice, to map metabolic pathways affected by treatment, and to discriminate between effects caused by treatment with agonists of the closely related PPARalpha and PPARgamma receptors.

Proteomic Profiling of Hepatic Endoplasmic Reticulum-associated Proteins in an Animal Model of Insulin Resistance and Metabolic Dyslipidemia

“…3). A recent proteomic analysis of the effect of obesity on hepatic protein expression showed ER60 was down-regulated in obese mice (30). Adeli et al (31) showed a direct association of ER60 with apoB in HepG2 cells.…”

Informatics Platform for Global Proteomic Profiling and Biomarker Discovery Using Liquid Chromatography-Tandem Mass Spectrometry

“…6c). A subset of these putative biomarkers were identified by CID sequencing and found to map to enzymes belonging to metabolic functions known to be elevated in the fasting state (35). For instance, three peptides mapped to betaine-homocysteine S-methyltransferase, an enzyme involved in homocysteine metabolism; two matched to the fatty-acid binding protein L-FABP, which is linked to the transport of lipids in liver; and two mapped to 10-formyltetrahydrofolate dehydrogenase, which mediates de novo biosynthesis of purine.…”

“…These adaptations are reflected at the protein level (35). As a general test of reproducibility, each tissue sample was analyzed in duplicate on two separate days, for a total of four datasets per sample.…”

Identification of novel molecular candidates for fatty liver in the hyperlipidemic mouse model, HcB19

“…Proteins induced in these mechanisms may be of great importance in advancing understanding of these processes, or even be potential therapeutic targets. To our knowledge, only a few studies addressed protein expression in NASH (9)(10)(11).…”