Abstract
The small intestine participates in lipid digestion, metabolism and transport. Cytosolic malic enzyme 1 (ME1) is an enzyme that generates NADPH used in fatty acid and cholesterol biosynthesis. Previous work has correlated liver and adipose ME1 expression with susceptibility to obesity and diabetes; however, the contributions of intestine-expressed ME1 to these conditions are unknown. We generated transgenic (Tg) mice expressing rat ME1 in the gastrointestinal epithelium under the control of the murine villin1 promoter/enhancer. Levels of intestinal ME1 protein (endogenous plus transgene) were greater in Tg than wildtype (WT) littermates. Effects of elevated intestinal ME1 on body weight, circulating insulin, select adipocytokines, blood glucose, and metabolism-related genes were examined. Male Tg mice fed a high-fat (HF) diet gained significantly more body weight than WT male littermates and had heavier livers. ME1-Tg mice had deeper intestinal and colon crypts, a greater intestinal 5-bromodeoxyuridine labeling index, and increased expression of intestinal lipogenic (Fasn, Srebf1) and cholesterol biosynthetic (Hmgcsr, Hmgcs1), genes. The livers from HF diet-fed Tg mice also exhibited an induction of cholesterol and lipogenic pathway genes and altered measures (Irs1, Irs2, Prkce) of insulin sensitivity. Results indicate that gastrointestinal ME1 via its influence on intestinal epithelial proliferation, and lipogenic and cholesterologenic genes may concomitantly impact signaling in liver to modify this tissue’s metabolic state. Our work highlights a new mouse model to address the role of intestine-expressed ME1 in whole body metabolism, hepatomegaly, and crypt cell proliferation. Intestinal ME1 may thus constitute a therapeutic target to reduce obesity-associated pathologies.
Highlights
The prevalence of obesity and its associated comorbidities has greatly increased over the past several decades [1]
Previous studies have shown that expression of cytosolic malic enzyme (ME1) and other lipogenic genes is elevated in the small intestine in animal models of diet-induced obesity [2,4,5] and that fatty acid and cholesterol biosynthesis and transport are up-regulated in the small intestine of diabetic, obese rats [6,7]
We examined the relative expression of a number of lipogenic genes in livers of WT and malic enzyme 1 (ME1)-Tg mice (Exp. 2). qRTPCR analysis showed significant increases in the mRNA abundance of Fatty Acid Synthase (Fasn), Srebf1, HMG-CoA Reductase (Hmgcr), Hmgcs1, Prkce and Ldlr (Ldl Receptor), decreased Apoe expression, and unchanged expression of Apoa1 and Cyp4a10 in livers of ME1-Tg compared to WT controls (Figure 5A, H)
Summary
The prevalence of obesity and its associated comorbidities has greatly increased over the past several decades [1]. The small intestine is an important organ for digestion, absorption and transport of dietary lipids, and may play an important role in conferring obesity and related pathologies [2,3]. Previous studies have shown that expression of cytosolic malic enzyme (ME1) and other lipogenic genes is elevated in the small intestine in animal models of diet-induced obesity [2,4,5] and that fatty acid and cholesterol biosynthesis and transport are up-regulated in the small intestine of diabetic, obese rats [6,7]. Germ-free mice are protected from diet-induced obesity, suggesting the influence of host-microbe interactions on intestinal lipid metabolism [8]. The collective findings point to an important role for intestinal metabolic pathways in the regulation of body glucose and lipid metabolism, and in the etiology of obesity and diabetes. A direct role for a specific intestinal lipid metabolic gene in the development of these conditions has not been established
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