Back to Course

Pathophysiology Videos

0% Complete
0/0 Steps
Lesson 3, Topic 1
In Progress

Lipid Metabolism

January 24, 2021
Lesson Progress
0% Complete

We will briefly review lipoprotein metabolism and some relevant clinical correlates.

Lipoprotein metabolism aims to transfer dietary sources of triglycerides to both muscle and adipose tissue for energy metabolism and storage, respectively. It also facilitates the cycling of cholesterol between the liver and peripheral tissues, a process critical for the formation of steroid hormones, cell membranes, and bile acids.

Bile salts emulsify fat globules into smaller fatty droplets that contain triglycerides and cholesterol esters.

Dietary triglycerides are then hydrolyzed into free fatty acids and monoacylglycerol in the intestinal lumen by pancreatic lipases. This enables the eventual transfer of triglycerides from the intestinal lumen into the circulatory system. The products of hydrolysis of triglycerides, i.e., free fatty acids and monoacylglycerol, are then repackaged into micelles, which then diffuse into the cytosol of the enterocyte. Once in the enterocyte, free fatty acids and monoacylglycerol are then resynthesized into triglycerides in preparation for delivery to the circulatory system.

Triglycerides, cholesterol esters, cholesterol, and apolipoprotein B-48 (Apo B-48) are then packaged into chylomicrons in the enterocyte. This concludes the formation of the first lipoprotein in the exogenous lipoprotein pathway.

Chylomicrons are secreted into the intestinal lymphatic system and then enter systemic circulation via the thoracic duct, thus bypassing portal circulation. By bypassing the liver, chylomicrons can be delivered directly to muscle and adipose tissue for metabolism. Once in the systemic circulation, HDL transfers apolipoprotein CII (Apo-CII) and apolipoprotein E (Apo-E) to chylomicrons.

Apo-E allows the binding of lipoproteins to specific LDL receptors or LDL-like receptors present in various tissues such as the liver and adrenal cortex. Apo-CII, on the other hand, is critical in activating lipoprotein lipase present in the capillary endothelium.

Chylomicrons reach adipose tissue and muscle, where lipoprotein lipase present on the endothelial lining of capillaries hydrolyzes triglycerides into free fatty acids and monoacylglycerol. Free fatty acids are then taken up by adipocytes and muscle cells for energy metabolism.

Chylomicron remnants, which are formed after this step, then release the previously acquired apo-CII, which was needed for lipoprotein lipase activity, back to HDL. This concludes the exogenous lipoprotein pathway, which facilitates the transfer of dietary sources of fatty acids from the intestine to muscle and adipose tissue for both storage and metabolism.

Chylomicron remnants, which contain a more substantial proportion of cholesterol and cholesterol esters compared to chylomicrons, bind to the hepatic LDL receptor and are transported into the liver for further processing.

Once in the liver, triglycerides, cholesterol esters, and Apo-B100 are repackaged into VLDL. VLDL in circulation, just like chylomicrons, receives Apo-E and Apo-CII from HDL.

VLDL is subsequently transported to adipose tissue and muscle, where again, lipoprotein lipase facilitates the hydrolysis of triglycerides into free fatty acids and monoacylglycerol. Free fatty acids can then be stored in adipose tissue or used for energy metabolism by muscle.

The loss of triglycerides from VLDL results in the formation of intermediate-density lipoproteins (IDL), which are also referred to as VLDL remnants. Again, Apo-CII will be released back to HDL after the formation of IDL.

IDL in circulation, with its surface bound Apo-E, has an affinity for tissues with LDL or LDL-like receptors (e.g., gonads and adrenal cortex). IDL binds to the hepatic LDL receptor, where it is taken up by the liver for further processing.

Apo-B100 and cholesterol esters are then repackaged into a new lipoprotein called LDL.

LDL binds LDL-like receptors in the gonads for gonadal steroidogenesis and the adrenal cortex for adrenal steroidogenesis. LDL can also bind LDL receptors present in muscle and adipose tissue, where it can be taken up for further processing.

 The lack of Apo-E on LDL allows it to have a longer circulating half-life. Ultimately, LDL tracks back to the liver to conclude the endogenous lipoprotein pathway. As you may recall, the primary purpose of the endogenous lipoprotein pathway is to transfer cholesterol and triglycerides from the liver to peripheral tissues for metabolism.

Now we will review some essential clinical pearls

Why do patients with hypertriglyceridemia, develop acute pancreatitis?

Pancreatic lipases hydrolyze elevated triglycerides present in the capillaries of the pancreas into free fatty acids and monoacylglycerol. Free fatty acids bind to serum calcium and cause direct damage to capillaries. Damage to capillary endothelium sets off a cascade of reactions, which leads to the formation of multiple microthrombi that subsequently clogs up capillaries and contributes to ischemia.

High levels of circulating serum chylomicrons cause extensive sludging of blood in the pancreatic capillaries, which leads to pancreatic ischemia and acidemia.

Also, free fatty acids activate trypsinogen, a critical step that finally initiates pancreatitis.

This concludes the endogenous lipoprotein pathway. Reverse cholesterol transport and other hyperlipidemia syndromes will be covered in a separate presentation.