ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways

Abstract

-Short-chain fatty acids (SCFAs), such as butyrate and propionate, are metabolic products of carbohydrate fermentation by the microbiota and constitute the main source of energy for host colonocytes. SCFAs are also important for gastrointestinal health, immunity, and host metabolism. Intestinally produced angiopoietin-like protein 4 (ANGPTL4) is a secreted protein with metabolism-altering properties and may offer a route by which microbiota can regulate host metabolism. Peroxisome proliferator-activated receptor (PPAR)-␥ has previously been shown to be involved in microbiota-induced expression of intestinal ANGPTL4, but the role of bacterial metabolites in this process has remained elusive. Here, we show that the SCFA butyrate regulates intestinal ANGPTL4 expression in a PPAR-␥-independent manner. Although PPAR-␥ is not required for butyrate-driven intestinal ANGPTL4 expression, costimulating with PPAR-␥ ligands and SCFAs leads to additive increases in ANGPTL4 levels. We suggest that PPAR-␥ and butyrate rely on two separate regulatory sites, a PPAR-responsive element downstream the transcription start site and a butyrate-responsive element(s) within the promoter region, 0.5 kb upstream of the transcription start site. Furthermore, butyrate gavage and colonization with Clostridium tyrobutyricum, a SCFA producer, can independently induce expression of intestinal ANGPTL4 in germ-free mice. Thus, oral administration of SCFA or use of SCFA-producing bacteria may be additional routes to maintain intestinal ANGPTL4 levels for preventive nutrition or therapeutic purposes.short-chain fatty acids; peroxisome proliferator-activated receptor-␥; fasting-induced adipose factor; angiopoietin-like protein 4; Clostridium tyrobutyricum THE HUMAN GASTROINTESTINAL (GI) tract has long been perceived as an organ with purely digestive functions. This perception has radically changed over the last decades as it emerged that the function of the GI tract is not only limited to energy uptake but also affects regulatory processes with wide-ranging systemic effects. These are either directly related to its digestive functions or independent ones impacting on local and systemic inflammation (reviewed in Ref. This crosstalk contributes among other things to the physiological state of the IEC including maturation and the integrity of the overall epithelial barrier (53). The importance of a well-regulated response to the intestinal microbiota and its metabolites has repeatedly been shown to be crucial to the health of the host (reviewed in Refs. 12 and 31).Mouse studies have also linked intestinal colonization to the capacity of energy utilization and weight gain (5, 6). One mechanism implied in this process is the regulation of angiopoietin-like protein 4 (ANGPTL4) expression in the intestinal epithelium. ANGPTL4 is a secreted protein with a variety of functions ranging from regulation of lipid and glucose homeostasis to inhibition of cell migration and angiogenesis (reviewed in Ref. 21). The NH 2 -terminal domain of ANGPTL4 inhibits lipoprote...

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

“…Though hnf4a mutant zebrafish have reduced in3.4 activity in the intestinal epithelium based on transgenic reporter assays, the transcript levels of the endogenous zebrafish angptl4 gene appears unaffected in both larval digestive tracts and adult IECs. The zebrafish genome encodes two additional HNF4 family members (hnf4b, hnf4g), and previous studies in mammals have shown Angptl4 can be regulated by other metabolically activated nuclear receptors (Staiger et al 2009;Korecka et al 2013). We hypothesize that loss of HNF4A function may lead to a metabolic imbalance leading to atypical or compensatory activation of other trans-and cis-factors that control expression of angptl4 and other genes in the intestine.…”

Obesity prevention of synthetic polysaccharides in high-fat diet fed C57BL/6 mice

“…Butyrate has been implicated to be the most important SCFAs for colonic cells due to its ability to serve as energy source for colonic epithelium as well as in regulating cell growth and differentiation, the restored barrier function of intestinal epithelial cell can prevent the penetration of endotoxin (LPS) (Litvak, Hwang, Evers, & Townsend, 2000;Mariadason, Corner, & Augenlicht, 2000). Furthermore, butyrate could increase the expression and activity of angiopoietin-like protein-4 in the intestinal cell (Korecka et al, 2013), which decreased lipoprotein lipase activity and increased lipolysis in white adipose tissue (Koliwad, Gray, & Wang, 2012). In addition, butyrate can also stimulate GLP-1 release from intestinal L-cell, resulting in decreases food intake or energy harvest (Yadav, Lee, Lloyd, Walter, & Rane, 2013).…”

Metabolic tinkering by the gut microbiome

“…114 The ability of L. paracasei to induce ANGPTL4 expression in vitro was mediated by PPAR-γ and PPAR-α activation which may in part be attributed to the SCFA butyrate. 115 Both L. rhamnosus and L. paracasei have been shown to modify gut microbiota composition and SCFA production which was correlated with altered hepatic lipid metabolism and circulating lipoprotein levels. 116 It will be important to understand whether systemic metabolic changes that occur upon Lactobacilli administration are responsible for enhancing cognitive function, as was observed for L. rhamnosus (JB-1).…”