Abstract
The intestinal microbiota enhances dietary energy harvest leading to increased fat storage in adipose tissues. This effect is caused in part by the microbial suppression of intestinal epithelial expression of a circulating inhibitor of lipoprotein lipase called Angiopoietin-like 4 (Angptl4/Fiaf). To define the cis-regulatory mechanisms underlying intestine-specific and microbial control of Angptl4 transcription, we utilized the zebrafish system in which host regulatory DNA can be rapidly analyzed in a live, transparent, and gnotobiotic vertebrate. We found that zebrafish angptl4 is transcribed in multiple tissues including the liver, pancreatic islet, and intestinal epithelium, which is similar to its mammalian homologs. Zebrafish angptl4 is also specifically suppressed in the intestinal epithelium upon colonization with a microbiota. In vivo transgenic reporter assays identified discrete tissue-specific regulatory modules within angptl4 intron 3 sufficient to drive expression in the liver, pancreatic islet β-cells, or intestinal enterocytes. Comparative sequence analyses and heterologous functional assays of angptl4 intron 3 sequences from 12 teleost fish species revealed differential evolution of the islet and intestinal regulatory modules. High-resolution functional mapping and site-directed mutagenesis defined the minimal set of regulatory sequences required for intestinal activity. Strikingly, the microbiota suppressed the transcriptional activity of the intestine-specific regulatory module similar to the endogenous angptl4 gene. These results suggest that the microbiota might regulate host intestinal Angptl4 protein expression and peripheral fat storage by suppressing the activity of an intestine-specific transcriptional enhancer. This study provides a useful paradigm for understanding how microbial signals interact with tissue-specific regulatory networks to control the activity and evolution of host gene transcription.
Highlights
The vertebrate intestine harbors a dense community of microorganisms that exerts a profound influence on distinct aspects of host physiology [1,2]
The presence of a gut microbiota results in a concomitant reduction in intestinal expression of Angiopoietin-like 4 (Angptl4, called Fiaf, Pgar, and Hfarp) [8,11], encoding a circulating peptide hormone that acts as a direct inhibitor of lipoprotein lipase (LPL) activity [12,13,14,15]
This restricted suppression leads to a significant increase in LPL activity and fat storage in adipose tissue of animals colonized with a microbiota, which is an effect abolished in mice lacking Angptl4 [8]
Summary
The vertebrate intestine harbors a dense community of microorganisms (gut microbiota) that exerts a profound influence on distinct aspects of host physiology [1,2]. Studies in gnotobiotic mice have indicated that microbial suppression of Angptl expression is restricted to the intestinal epithelium and is not observed in other tissues that express Angptl, such as liver and adipose tissue This restricted suppression leads to a significant increase in LPL activity and fat storage in adipose tissue of animals colonized with a microbiota, which is an effect abolished in mice lacking Angptl4 [8]. These results have established Angptl as a key host factor mediating the microbial regulation of host energy balance and have raised considerable interest in defining the mechanisms underlying the tissue-specific and microbial regulation of Angptl expression. The importance of understanding mechanisms regulating Angptl production is further underscored by reports suggesting that human ANGPTL4 functions as an important determinant of plasma TG levels [16,17] and by Angptl4’s additional functions in Author Summary
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