Abstract
BackgroundObesity and associated hormonal disturbances are risk factors for colon cancer. Cytosolic Malic Enzyme (ME1) generates NADPH used for lipogenesis in gastrointestinal (GI), liver and adipose tissues. We have reported that inclusion of soy protein isolate (SPI) in the diet lowered body fat content and colon tumor incidence of rats fed AIN-93G diet, while others have demonstrated SPI inhibition of rat hepatic ME1 expression. The present study examined the individual and combined effects of dietary SPI and absence of ME1 on: 1) serum concentrations of hormones implicated in colon cancer development, 2) expression of lipogenic and proliferation-associated genes in the mouse colon and small intestine, and 3) liver and adipose expression of lipogenic and adipocytokine genes that may contribute to colon cancer predisposition.MethodsWeanling wild type (WT) and ME1 null (MOD-1) male mice were fed high-fat (HF), iso-caloric diets containing either casein (CAS) or SPI as sole protein source for 5 wks. Somatic growth, serum hormone and glucose levels, liver and adipose tissue weights, GI tissue parameters, and gene expression were evaluated.ResultsThe MOD-1 genotype and SPI-HF diet resulted in decreases in: body and retroperitoneal fat weights, serum insulin, serum leptin, leptin/adiponectin ratio, adipocyte size, colon mTOR and cyclin D1 mRNA abundance, and jejunum FASN mRNA abundance, when compared to WT mice fed CAS-HF. Regardless of diet, MOD-1 mice had reductions in liver weight, liver steatosis, and colon crypt depth, and increases in adipose tissue expression of IRS1 and IRS2, compared to WT mice. SPI-HF diet reduced ME1 gene expression only in retroperitoneal fat.ConclusionsData suggest that the pharmacological targeting of ME1 or the inclusion of soy protein in the diet may provide avenues to reduce obesity and its associated pro-tumorigenic endocrine environment and improve insulin sensitivity, potentially disrupting the obesity-colon cancer connection.
Highlights
The prevalence of overweight and obesity has escalated during the last several decades [1]
Malic Enzyme 1 (ME1) gene that encompasses exons 10–13 (Fig. 1A). This internal duplication results in formation of an aberrant ME1 mRNA encoding an unstable ME1 protein variant that does not accumulate to appreciable levels in cytoplasm [33]
During weeks 5–8, soy protein isolate (SPI)-HF-fed wild type (WT) mice showed significantly reduced weight gains compared to WT counterparts fed CAS-HF diet; MOD-1 mice had less weight gains than corresponding WT mice, regardless of diet (Fig. 2A)
Summary
The prevalence of overweight and obesity has escalated during the last several decades [1]. Insulin-induced lipogenesis is a known survival mechanism by which colorectal cancer cells maintain growth, escape apoptosis and acquire chemo-resistance [8,9,10,11] This pathway is known to be regulated by dietary and hormonal factors [12]. Up-regulation of insulin signaling in liver and adipose tissues increases steatosis and fat mass, respectively and the same pathway supports growth and chemo-resistance of cancer cells [13] In this regard, pharmacologic inhibition or knockdown of Fatty Acid Synthase (FASN) and Acetyl-CoA Carboxylase (ACC), key enzymes of lipid synthesis in rapidly proliferating cells, can lead to cancer cell growth arrest and apoptosis [8,14,15]. The present study examined the individual and combined effects of dietary SPI and absence of ME1 on: 1) serum concentrations of hormones implicated in colon cancer development, 2) expression of lipogenic and proliferation-associated genes in the mouse colon and small intestine, and 3) liver and adipose expression of lipogenic and adipocytokine genes that may contribute to colon cancer predisposition
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