Cholesterol Homeostasis

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Blood cholesterol levels (average healthy adult)

< 200 mg/dL (cholesterol levels vary more than tightly controlled glucose levels)

• 2 sources of cholesterol: biosynthesis and dietary

REGULATORY POINTS

1. Cholesterol Biosynthesis

• Occurs in most tissues, but primarily in liver

2. LDL receptors

• LDL transports cholesterol throughout body

3. Bile acid biosynthesis

• Sole mechanism for cholesterol clearance

1. CHOLESTEROL BIOSYNTHESIS

HMG CoA Reductase Regulation

i. Transcription

• SREBP-2 binds sterol regulatory element (SRE) and enhances transcription
• SREBP-2/SCAP release from Golgi inhibited by excess intracellular cholesterol
  ii. Translation
• Mevalonate (biosynthetic intermediate) produces non-sterol metabolites that block RNA translation in the cytosol
  iii. Proteolysis
• Excess cholesterol stimulates reductase proteolysis by ubiquitination
  iv. Covalent modification
• Insulin promotes dephosphorylation and activation of reductase
• Glucagon promotes phosphorylation and inactivation of reductase (AMP-dependent pathway)

Acyl CoA cholesterol acyltransferase (ACAT)

Esterifies cholesterol in hepatic cells: "There is A CAT in the liver"

2. LDL RECEPTORS

LDL: main cholesterol carrier in the body

• Excess cholesterol inhibits LDL-receptor synthesis

3. BILE ACID BIOSYNTHESIS

HDL: picks up plasma cholesterol released by cell death or membrane turnover

• Contains lecithin cholesterol acyl transferase (LCAT): esterifies cholesterol
• Delivers esterified cholesterol to liver cell
• Liver converts esterified cholesterol to bile salts: secreted into intestine

CLINICAL CORRELATIONS

Diabetics taking exogenous insulin

Have high levels of HMG CoA reductase in hepatocytes

Statins

Class of drugs that inhibit HMG CoA reductase: combat high cholesterol

Cholestyramine

Bile acid binding resin: binds bile salts in intestine and prevents reabsorption

• Initiates feedback mechanism: increases bile production, cholesterol and LDL receptor synthesis
• Combats high cholesterol

Full-Length Text

• Here we will learn how cholesterol levels are regulated in the body.

• To begin, start a table.

• Denote that in an average healthy adult, blood cholesterol ranges from 120 to 210 mg/dl.

• Now, denote the key regulatory points in cholesterol homeostasis:
  • Cholesterol biosynthesis, which primarily occurs in the liver.
  • LDL receptors, low-density lipoproteins transport cholesterol throughout the body.
  • Bile acid biosynthesis, the sole mechanism for cholesterol clearance.
  • Fluctuations in blood cholesterol initiate regulation of these components.

We'll start with the biosynthetic pathway, which occurs in most tissues.

• First, recall that we obtain cholesterol from two sources: the biosynthetic pathway and diet.

• Imagine a scale with dietary cholesterol intake on one side and the biosynthesis on the other.
  • When dietary cholesterol increases biosynthesis decreases.
  • When dietary cholesterol decreases, biosynthesis increases.

Now, let's draw the substrates of cholesterol biosynthesis.

• Show that acetyl CoA and acetoacetyl CoA combine to form HMG CoA.

• Now the committed step: show that HMG CoA reductase, the key regulated enzyme, converts HMG CoA to mevalonate in the cytosol.

• Show that mevalonate converts to cholesterol after multiple steps.

• Now, return to our table and denote that HMG CoA reductase (and the biosynthetic pathway) is controlled in the following ways:
  • Transcription
  • Translation
  • Proteolysis
  • Covalent modification

Let's illustrate this in a liver cell, a major site of cholesterol synthesis.

• Draw an invaginating plasma membrane.
  • We will explain why shortly.

• For now, label the cytosol and the extracellular space.

• Now, draw a nucleus.

Let's start with transcriptional-level regulation.

• Within the nucleus, draw portion of DNA labeled HMG CoA reductase gene.

• Label a short portion of the gene as sterol regulatory element (SRE); it is located upstream of the DNA sequence that encodes the reductase.

• Next, draw a transcription factor called SREBP-2 (SRE-binding protein) bound to the SRE.

• Write that SREBP-2 enhances transcription of the reductase.

• And show transcription of the gene to mRNA.

• To understand how intracellular cholesterol levels affect SREBP-2 binding,draw an endoplasmic reticulum.

• Show SREBP-2 is bound to the membrane.

• And show that it associates with a protein called SREBP cleavage activating protein (SCAP).

• Next, draw a Golgi apparatus.

• Indicate that when cholesterol levels are low, the SREBP-2/SCAP complex is released to the Golgi.

• Write that here, SREBP-2 is cleaved.
  • Show that this allows it to enter the nucleus.

• So, for our first form of regulation, indicate that excess cholesterol blocks SREBP-2/SCAP release from the ER, which ultimately reduces transcription of HMG CoA reductase.

Now, for translation-level regulation.

• Show that the mRNA transcript from the nucleus is translated to the reductase in the cytosol when cholesterol levels are low.

• Next, show that mevalonate produces non-sterol metabolites (some of which are downstream intermediates in the pathway), which block translation.

Now, for proteolysis.

• Show that, quite simply, an excess of cholesterol stimulates proteolysis of HMG CoA reductase via ubiquitination.

Finally, covalent modification, which is mediated by insulin and glucagon.

• Draw a phosphorylated HMG CoA reductase and label it inactive.

• Show that insulin, which is secreted when plasma glucose is abundant, promotes the dephosphorylation and activation of HMG CoA reductase.
  • It also promotes transcription of the enzyme in the liver.

• Show that glucagon promotes the opposite via an AMP-dependent pathway.

• Now, as a clinical correlation, consider what happens with diabetics who take exogenous insulin.
  • Write that diabetics taking exogenous insulin have high levels of HMG CoA reductase in their hepatocytes because insulin promotes HMG CoA reductase transcription and activation.
  • Next, write that statins are a class of drugs often prescribed to combat high cholesterol. They inhibit HMG CoA reductase.

We've learned how biosynthesis is controlled, but what happens to the excess cholesterol?

• Show that it is esterified, which makes it more hydrophobic for efficient packaging.

• Indicate that the liver enzyme acyl-CoA-cholesterol acyltransferase (ACAT) esterifies cholesterol intracellularly.
  • As a mnemonic, indicate that we can remember the localization of these isozymes by saying that there is "A-CAT in the liver."

This brings us to the last 2 regulatory points: LDL receptors and bile acids.

We'll start with LDL receptors.

• Draw a representative LDL (low density lipoprotein) in the extracellular space.

• Write that it is the main cholesterol carrier in the body, and regulates cholesterol synthesis in the peripheral tissues.

• Show it bound to an LDL receptor on the invaginating portion of the membrane.
  • LDL's bind these receptors and are endocytosed.

• Now, show that excess cholesterol inhibits the synthesis of LDL receptors.
  • Thus, new plasma cholesterol is not taken up under these conditions.

• Finally, draw an HDL (high density lipoprotein) in the extracellular space; it picks up plasma cholesterol released after cell death or membrane turnover.

• Show that lecithin cholesterol acyl transferase (LCAT) is localized here; it esterifies cholesterol in HDL.

• Show that this HDL delivers esterified cholesterol to the liver cell.

• Indicate that the liver converts this esterified cholesterol to bile acids and then bile salts, which are secreted into the intestine.

• Show that it is the only mechanism for cholesterol excretion in the body.

• As a clinical correlation, write that cholestyramine is a drug prescribed for high cholesterol.
  • It is a bile acid binding resin, and binds bile salts in the intestine, thus preventing their reabsorption.
  • This initiates a feedback mechanism: the liver produces more bile, which requires more cholesterol and more LDL receptors.