Fall 2015 – Cholesterol Homeostasis I

The Burmese python (Python molurus) is a fascinating animal which is able to digest large meals, which it rapidly digests. This swift digestion is taxing on many organs including the heart, liver, and stomach. Breakdown of the meal causes a dramatic increase in lipid levels in the python serum after only a day, up to a 50-fold increase. The levels of lipids in the python would induce lipotoxicity in other animals; however, the python is able to avoid the toxic effects of elevated lipid levels and to clear the lipids from its serum in a matter of days. The ability to prevent lipotoxicity after feeding, coupled with the efficient clearing of lipids from its serum, makes the Burmese python a unique model organism for studying lipid metabolism. It is for this reason the Python Project has decided to focus its efforts on studying the python and how its liver is responsible for these feats. Understanding how the animal is able to metabolize lipids in such a unique way could provide insight into treating diabetes and obesity in humans.*

To understand what makes lipid metabolism so unique in the python, it is important to consider how animals metabolize lipids.  When an animal eats a fatty meal, fatty chime—partially undigested food—enters the duodenum. This causes the release of cholecystokinin and secretin. The released secretin in the blood stimulates the liver to produce bile, which is stored in the gallbladder. Bile acids released from the gallbladder act emulsify fats from the chyme by forming micelles around the lipids. The bile salts act to break down dietary triacylglycerides, after which they are repackaged as triglycerides (TAGs) for blood transport. The TAGs associate with phospholipids and apolipoproteins to form a chylomicron, which can be taken up by the intestine into the blood. These apolipoproteins transport TAGs to the liver and peripheral tissues. In most animals, having too many fats enter this pathway leads to an accumulation of lipids in peripheral tissue casing lipotoxicity. Fat can accumulate in the liver, muscle, and around blood vesicles. This can lead to a host of problems, including insulin resistance, causing diabetes, or non-alcoholic fatty liver disease. However, the python is able to avoid the accumulation of fats in peripheral tissue, and thus lipotoxicity .*

The exact mechanism by which the Burmese python prevents the accumulation of lipids in the peripheral tissue is unknown. However, there are a few possibilities. Fatty acids are known to be metabolized by beta-oxidation, so the python liver may undergo extremely high amounts of beta-oxidation. This still leaves high amounts of cholesterol and other lipids unaccounted for. Cholesterol, however, is a precursor to bile acids. The only significant mechanism for cholesterol elimination is the conversion of them into bile acids in the liver. The conversion of cholesterol into bile acids would also facilitate further digestion of TAGs by emulsifying them to allow uptake into the blood.*

We therefore focused our research on genes that are responsible for moving lipids from the blood into the hepatocyte, converting lipids into cholesterol, modifying cholesterol to become bile acids, and removal of bile acids from the hepatocyte.  16 genes were chosen representing these processes, a small fraction of those involved in the entire process of removing lipids from the blood.  Data revealed an increase in expression of genes that encode lipid transporters at 1 day after feeding.  Interestingly, at 1 and 3 days after feeding expression of most genes involved in bile acid synthesis was decreased.  However, expression of several genes encoding bile acid export proteins was increased at 3 days after feeding.  The students concluded that there should be an increase in bile acid synthesis genes and that perhaps the time point at which they increase is earlier than 1 day after feeding or between 1 and 3 days.  Six students who will be continuing their work in Spring 2016 decided that the time points should be expanded.  Therefore, we will be continuing our research on the mechanisms mediating cholesterol homeostasis in the liver next semester.

*adapted from a research paper written by Alex Tate, a student in the Fall 2015 Python Project

To view the Mindomo presentation that summarizes the findings from the Spring 2016 semester, click below:

Fall 2015 Concept Map