Cholesterol plays a crucial role in our bodies, from cell membranes to hormone production. This section dives into how our bodies make, use, and regulate cholesterol, as well as the lipoproteins that transport it through our bloodstream.
Understanding cholesterol metabolism is key to grasping lipid-related health issues. We'll explore the enzymes involved in cholesterol synthesis, the different types of lipoproteins, and how our bodies balance cholesterol levels through various regulatory mechanisms.
Cholesterol Biosynthesis and Regulation
HMG-CoA Reductase and the Mevalonate Pathway
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- HMG-CoA reductase catalyzes the rate-limiting step in cholesterol biosynthesis
- Converts HMG-CoA to mevalonate
- Regulated through feedback inhibition by cholesterol
- Mevalonate pathway produces cholesterol and other isoprenoids
- Starts with acetyl-CoA and proceeds through multiple enzymatic steps
- Involves condensation of three acetyl-CoA molecules to form HMG-CoA
- Produces important intermediates (isopentenyl pyrophosphate, farnesyl pyrophosphate)
- Statins inhibit HMG-CoA reductase to lower cholesterol levels
- Competitive inhibitors that mimic the structure of HMG-CoA
- Reduce LDL cholesterol by up to 60%
- Side effects can include muscle pain and liver damage
Regulation of Cholesterol Biosynthesis
- Transcriptional regulation through sterol regulatory element-binding proteins (SREBPs)
- SREBPs activate genes involved in cholesterol synthesis when levels are low
- Insulin promotes SREBP activation, increasing cholesterol synthesis
- Post-translational regulation of HMG-CoA reductase
- Phosphorylation by AMP-activated protein kinase (AMPK) inhibits the enzyme
- Ubiquitination and degradation occur when cholesterol levels are high
- Feedback inhibition by cholesterol and its derivatives
- Oxysterols bind to liver X receptors (LXRs) to suppress cholesterol synthesis
- Bile acids activate farnesoid X receptor (FXR) to reduce cholesterol production
Lipoproteins
Structure and Function of Lipoproteins
- Lipoproteins transport lipids through the bloodstream
- Consist of a hydrophobic core (triglycerides, cholesterol esters) and a hydrophilic surface (phospholipids, free cholesterol, apolipoproteins)
- Low-density lipoproteins (LDL) deliver cholesterol to peripheral tissues
- Often called "bad cholesterol" due to its role in atherosclerosis
- Contain apolipoprotein B-100 as their primary apolipoprotein
- High-density lipoproteins (HDL) remove excess cholesterol from tissues
- Known as "good cholesterol" for its protective role against cardiovascular disease
- Contain apolipoprotein A-I as their main apolipoprotein
- Very low-density lipoproteins (VLDL) transport triglycerides from the liver to tissues
- Precursors to LDL particles
- Rich in triglycerides and contain apolipoprotein B-100
Chylomicrons and Apolipoproteins
- Chylomicrons transport dietary lipids from the intestine to tissues
- Largest lipoprotein particles
- Contain apolipoprotein B-48, unique to intestinal cells
- Apolipoproteins serve multiple functions in lipoprotein metabolism
- Act as structural components of lipoproteins
- Facilitate lipoprotein interactions with cell surface receptors
- Activate or inhibit enzymes involved in lipoprotein metabolism
- Key apolipoproteins include:
- ApoA (found in HDL)
- ApoB (found in LDL, VLDL, and chylomicrons)
- ApoC (found in VLDL and chylomicrons)
- ApoE (involved in cholesterol clearance and found in multiple lipoproteins)
Cholesterol Metabolism and Excretion
Reverse Cholesterol Transport
- Reverse cholesterol transport removes excess cholesterol from peripheral tissues
- HDL particles accept cholesterol from cells via ATP-binding cassette transporter A1 (ABCA1)
- Lecithin-cholesterol acyltransferase (LCAT) esterifies free cholesterol in HDL
- Cholesteryl ester transfer protein (CETP) transfers cholesterol esters to other lipoproteins
- Scavenger receptor class B type I (SR-BI) mediates selective uptake of cholesterol by the liver
- Allows for cholesterol excretion through bile or conversion to bile acids
- Reverse cholesterol transport plays a crucial role in preventing atherosclerosis
- Removes cholesterol from arterial walls
- Explains the protective effect of high HDL levels against cardiovascular disease
Bile Acids and Steroid Hormones
- Bile acids facilitate digestion and absorption of dietary lipids
- Synthesized from cholesterol in the liver
- Primary bile acids (cholic acid, chenodeoxycholic acid) conjugated with glycine or taurine
- Secreted into the intestine and largely reabsorbed (enterohepatic circulation)
- Cholesterol serves as a precursor for steroid hormone synthesis
- Adrenal glands produce cortisol and aldosterone
- Gonads produce sex hormones (testosterone, estrogen, progesterone)
- Biosynthesis involves multiple enzymatic steps and intermediates
- Regulation of bile acid and steroid hormone synthesis
- Cholesterol 7α-hydroxylase catalyzes the rate-limiting step in bile acid synthesis
- Steroidogenic acute regulatory protein (StAR) controls cholesterol transport for steroidogenesis
- Feedback inhibition by end products helps maintain homeostasis