Stop the fat

Holding back intestinal lipids from going into circulation in a zebrafish

 
Juvenile zebrafish
Credit:NIH

A research team at the University of Utah recently discovered a protein in zebrafish that apparently determines how long the intestine stores dietary lipids before they are delivered to tissues and the bloodstream. This delay, it seems, ultimately reduces blood cholesterol and triglyceride levels. The team’s findings were reported in the Journal of Lipid Research.

After we eat a meal, our intestinal cells repackage the cholesterol and fatty acids from food so that they can be delivered to other parts of the body. Amnon Schlegel, who led the research team, says the intestine “appears to serves as a transient reservoir of absorbed lipids.” In this study, the zebrafish version of liver X receptor a, or LXRa, a protein that inhibits cholesterol absorption and promotes reverse cholesterol transport when activated, was identified as a previously unrecognized pacesetter of intestinal lipid transport.

 
After digestion and micellar suspension ofneutral lipids in the lumen of the intestine, lipids are absorbed across theapical surface of enterocytes. Fatty acids and cholesterol are re-esterifiedinto triacylglycerol, phospholipids and cholesteryl esters that are repackagedinto chylomicron, which are secreted across the basolateral surface. Liver Xreceptors, nuclear receptors for oxysterols, set the pace of transport ofingested lipids across the intestine by directing the development of atemporary storage depot of lipids in cytoplasmic lipid droplets, in part, byinducing expression of Acsl3, an enzyme that directs acyl chains intoincorporation in lipid droplets. This delay in delivery of absorbed lipidsprotects animals from high-fat-diet-induced dyslipidemia and hepatic steatosis.  

Based on their own studies and the studies of others, Schlegel’s team knew that high bloodstream levels of triglycerides right after a meal were “strongly predictive of cardiovascular disease,” Schlegel said. So the team was interested in learning more about the molecules that control the pace of lipids returning to the bloodstream.

The team decided to study zebrafish, because their larvae are transparent and therefore can be stained for intestinal, liver and vascular lipids. The team also studied enterocytes, intestinal absorptive cells that have roles in secretion and transport of lipids.

Three types of larvae — wild type, those that had sustained activation of the zebrafish LXR and those that had no LXR activity — were fed a high-fat meal and then stained. In the wild type larvae and larvae with no LXR activity, the ingested lipids were located in the vasculature. In stark contrast, the lipids in larvae with sustained LXR activity did not have the same staining pattern, suggesting that something was holding back the lipids from returning to circulation. Later examination of fed larvae at three time points over three days showed complete digestion of lipids in wild type larvae and those without LXR activity, whereas there were still lipids persisting in the intestines in the larvae with sustained LXR activity.

These results support the idea that overexpression of the gene delays lipid transport and absorption.

“Our genetic evidence in zebrafish indicates that sustained activation of LXR in the intestine alone protects the animals from increased blood and liver cholesterol and triglyceride levels caused by high-fat feeding,” Schlegel concludes.

“This is a crucial finding, because many LXR-activating compounds have not advanced to drug development, because they trigger accumulation of neutral lipids in the liver, a process termed hepatic steatosis. It is conceivable that such intestine-limited LXR-activating drugs would be useful in treating human lipid disorders. Indeed, while several excellent drug classes — statins foremost — are available to treat these disorders and reduce the risk of cardiovascular disease, these drugs do not fully lower the chance of developing cardiovascular disease.”

He added that not all patients tolerate existing cholesterol-lowering drugs and “intestinal LXR activators hold the promise of offering an alternative treatment.”

The researchers concede that long-term studies are needed to see what effects zebrafish LXRa overexpression has on zebrafish life span, fertility, atherogenesis and obesity. There is also the question of what other molecules may affect the pace of lipid absorption, and the researchers already have begun a comprehensive follow-up study to determine if genetic activation of LXR in the intestine of zebrafish prevents atherosclerosis.

Mary L. ChangMary L. Chang (mchang@asbmb.org) is publications manager for ASBMB.