Unknown,Transcriptomics,Genomics,Proteomics

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Expression data from livers of high fat fed rats treated with ACC inhibitor PF-04923503

ABSTRACT: Fundamental alterations in lipid metabolism including increased rates of de novo lipogenesis (DNL), reduced fatty acid oxidation (FAOX) and ectopic lipid accumulation in skeletal muscle and liver are characteristic of type 2 diabetes mellitus (T2DM) and have been hypothesized to directly contribute to the molecular pathogenesis of the disease. Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, the rate limiting substrate for DML and key regulator of FAOX. ACC inhibitors have the potential to pharmacologically rebalance these metabolic alterations. In the present study, PF-04923503, a potent dual ACC1/ACC2 inhibitor with properties optimized for in vivo studies, suppressed levels of malonyl-CoA in primary hepatocytes, rat skeletal muscle ex vivo, as well as rat liver and skeletal muscle in vivo. This impact on malonyl-CoA was directly correlated (r2>0.9) with reduced hepatic DNL and inversely correlated with incresed rates of FAOX (r2>0.9). The pharmacological eccfect of PF-04923503 persisted with chronic treatment. High-fat fed rats treated with PF-04923503 for six weeks showed dose-dependent reductions in skeletal muscle and liver lipid accumulation. These changes correlated directly with markers for improved insulin sensitization. However, liver gene expression indicates that pharmacological inhibition results in compensation by up-regualtion of genes involved with DNL. These results suggest that pharmacological inhibition of ACC may have utility to help rebalance metabolic abnormalities in T2DM and improve insulin sensitivity. Differential gene expression was assessed by Affymetrix microarray experiments for 15 liver samples across 3 pharmacological treatment groups (vehicle control 0.5% methylcellulose had 5 samples, PF-04923503 10mpk had 5 samples, PF-04923503 30mpk had 5 samples)

ORGANISM(S): Rattus norvegicus

SUBMITTER: William Esler

PROVIDER: E-GEOD-28058 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Lysine malonylation is an evolutionarily conserved PTM from bacteria to mammals and involves malonyl-coenzyme (CoA) as a cofactor. Since the malonyl group has an acidic carboxylic group under physiological pH, malonylated lysine is negatively charged, which might impact on protein function and enzymatic activities. Like other short-chain acyl-CoAs, malonyl-CoA can be synthesized from its corresponding short-chain acyl salt, malonate, catalyzed by malonyl-CoA synthetase (Witkowski et al., 2011). In addition, malonyl-CoA can be produced during the carboxylation of acetyl-CoA by acetyl-CoA carboxylase (ACC), the carboxylation of acetyl-CoA by propionyl-CoA carboxylase, and the β-oxidation of old-chain-length dicarboxylic acids (Peng et al., 2011). Most studies on Kmal have been performed in mammalian systems and identified thousands of malonylated sites, revealing its role in the progress of diseases like type 2 diabetes, schizophrenia, and cardiac hypertrophy (Du et al., 2015; Smith et al., 2022; Wu et al., 2022). There has been increasing interest in dissecting the regulatory roles of Kmal in several bacterial species, such as Escherichia coli (Qian et al., 2016), Bacillus amyloliquefaciens (Fan et al., 2017), Mycobacterium tuberculosis (Bi et al., 2022), and Staphylococcus aureus (Shi et al., 2021), which demonstrates that Kmal exists in diverse prokaryotic organisms and participates in the regulation of various physiological processes. Even so, whether Kmal exists and affects protein functions in streptococci remains unknown. S. mutans is considered to be the most prevalent and cariogenic species in active carious lesions of humans, residing primarily in dental plaque, which is a biofilm that forms on the tooth surfaces. During the past decades, studies of S. mutans have focused on revealing the molecular mechanisms underlying the robust biofilm formation on tooth surfaces, the metabolism of a wide variety of carbohydrates obtained from the host diet, and the adaption of numerous environmental challenges (Lemos et al., 2019). Several studies have been performed to reveal the roles of PTMs in biofilm and cariogenic virulence. Wang et al. found that the phosphorylation of VicR could inhibit the expression of the glucosyltransferases gtfBC, thereby reducing the synthesis of extracellular polysaccharides (EPS), the major component of cariogenic biofilm (Wang et al., 2021). Acetylome study on the S. mutans depicted that acetylated substrates were globally altered in the biofilm state compared to the planktonic state, and the acetylated GtfBC showed decreased activities (Lei et al., 2021; Ma et al., 2021). Our previous study revealed that the S-glutathionylation of a thioredoxin-like protein is important for interspecies competition and cariogenicity of S. mutans(Li et al., 2020). These results suggest that various PTM types exist in S. mutans and participate in diverse physiological processes. The genome of S. mutans UA159 codes an acetyl coenzyme A carboxylase (ACC), which could synthesize malonyl-CoA through the carboxylation of acetyl-CoA (Ajdić et al., 2002), implying the existence of malonylation in this bacterium. Therefore, this study aimed to confirm the existence of Kmal in S. mutans and identify the malonylated sites globally. The present findings provide a systematic view of the functional roles of Kmal in various metabolic pathways of S. mutans.

Project description:Fatty acid synthesis is closely linked to nutrient availability and cellular energetic status. The committed step in fatty acid synthesis is the acetyl CoA carboxylase. Eukaryotes have two genes encoding acetyl CoA carboxylases, one encoding a cytosolic enzyme and another coding for a mitochondrial enzyme. They catalyze the synthesis of malonyl CoA in the cytosol and the mitochondria, respectively. While cytosolic malonyl CoA is the precursor for fatty acid synthesis, mitochondrial malonyl CoA controls the transfer of fatty acyl group into the mitochondria by inhibiting carnitine/palmitoyl transferase activity and thus, regulates Î²-oxidation. In Saccharomyces cerevisiae, Î²-oxidation is restricted to the peroxisomes, raising the question of the function of the mitochondrial isoform (HFA1). In this study, we replaced the cytosolic Acc1 with Hfa1 expressed in the cytosol by removing the mitochondrial leader peptide, under control of the HFA1 promoter. We studied fatty acid synthesis and transcription profiles in this strain during starvation for carbon or nitrogen, using glucose or ethanol as the carbon source. Under all the conditions studied, the key sensor of energetic status, Snf1, was activated, indicating active inhibition of fatty acid synthesis. The pool size of fatty acids was smaller when Acc1 was replaced with truncated Hfa1 for fatty acid synthesis. Yet, the transcription profiles were similar in both the cases. These results point towards the conclusion that Hfa1 is either catalytically less efficient or it is more sensitive to inhibition by Snf1. Gene expression from a strain of Saccharomyces cerevisiae where cytosolic fatty acid synthesis occurs by mitochondrial acetyl CoA carboxylase (without its mitochondrial leader peptide) is compared with that in a reference strain while growing in chemostats on carbon or nitrogen starvation using glucose or ethanol as the carbon source. There are two strains (reference or mutant), two carbon sources (glucose or ethanol) and two limitations (carbon or nitrogen), resulting in 8 comparisons. Each array was performed in duplicate, resulting in 16 CEL files. Growth was limited by either carbon or nitrogen. When carbon was the limited nutrient, we tested growth on either glucose or ethanol (both using ammonium sulfate as the nitrogen source). When ammonium sulfate was limiting, we used either glucose or ethanol as the carbon source.

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Expression data from livers of high fat fed rats treated with ACC inhibitor PF-04923503

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