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Transcription factor PlagL2 regulates steps in chylomicron metabolism

ABSTRACT: Enterocytes assemble dietary lipids into chylomicron particles that are taken up by intestinal lacteal vessels and peripheral tissues. Although chylomicrons are known to assemble in part within membrane secretory pathways, the modifications required for efficient vascular uptake are unknown. We report that the transcription factor Pleomorphic adenoma gene-like 2 (PLAGL2) is essential for this aspect of dietary lipid metabolism. PlagL2-/- mice die from post-natal wasting owing to failure of fat absorption. Lipids modified in the absence of PlagL2 exit from enterocytes but fail to enter interstitial lacteal vessels. Dysregulation of enterocyte genes closely linked to intracellular membrane transport identified candidate regulators of critical steps in chylomicron assembly. PlagL2 thus regulates essential and poorly understood aspects of dietary lipid absorption and its deficiency represents an authentic animal model with implications for amelioration of obesity or the metabolic syndrome. Keywords: gene expression profiling analysis

ORGANISM(S): Mus musculus

PROVIDER: GSE9123 | GEO | 2007/09/22

SECONDARY ACCESSION(S): PRJNA102661

REPOSITORIES: GEO

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Project description:Despite the crucial function of the small intestine for nutrient uptake our understanding of the molecular events underlying the digestive function is very rudimentary. For example, it has only recently become evident that not all absorbed triacylglycerol (TAG) is immediately secreted in the form of chylomicrons (CM) by enterocytes. Instead, especially after high-fat challenges, parts of the re-synthesized TAG can be packaged into cytosolic lipid droplets (CLD) for transient storage in the endothelial layer of the small intestine. The reasons for this intermediate storage of TAGs are currently not completely understood. Several mechanisms, including alleviating lipotoxicity to enterocytes, limits in the rate of CM assembly or smoothening of the post-prandial peaks of blood hypertriglyceridemia have been suggested to explain this intermediate storage of TAG in CLD. Interestingly, rather than being evenly distributed across the small intestine, the proximal jejunum exhibits the highest TAG storage and CM secretion. Once stored in CLD, lipids are either remobilized in the inter-prandial phase or by various stimuli, e.g. a sequential meal containing either lipids or glucose. After remobilization, a triglyceride peak can be observed in the form of plasma CM well before lipids from the second meal have been digested in the intestinal lumen. To synthesize CM with lipids from CLD, CLD TAG have to be hydrolyzed to be transported across the ER membrane which can either be achieved by cytoplasmic TAG lipolysis or lipophagy. We hypothesize that correlating enzymatic activities of hydrolases with the reported distribution of TAG storage and chylomicron secretion in different sections of the small intestine is a promising strategy to pinpoint the key players in TAG remobilization. To rank hydrolases based on their relative activity in the different sections of the small intestine we have harnessed a serine hydrolase specific activity-based labeling strategy to label active hydrolases in freshly harvested enterocytes. Enrichment of activity labeled enzymes over control samples and abundance of enriched hydrolases from individual small intestine sections was analyzed using quantitative proteomics, resulting in a ranking of the most active hydrolases in 11 fractions of murine small intestine. Moreover, several clusters of enzymes showing similar activity distribution along the small intestine were identified.

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Transcription factor PlagL2 regulates steps in chylomicron metabolism

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