Bile Acids

Question 1

Describe the production of bile acids. What pathways are involved?

Answer 1

•Produced from cholesterol in hepatocytes
• Classic pathway (produces Cholic Acid; CA) and Alternative pathway (produces Chenodeoxycholic Acid; CDCA)
- each pathway has their own rate limiting enzyme

Question 2

What is the difference between bile acids and bile salts?

Answer 2

Primary bile acids are conjugated with either TAURINE or GLYCINE (++) to form bile salt before they are secreted from hepatocytes

Question 3

Give the 4 general steps in enterohepatic circulation

Answer 3

1. Bile salts are secreted by liver - 95% are old, recycled bile salts; 5% are newly synthesized
2. 95% of bile salts are reabsorbed by the small intestine
3. Reabsorbed bile salts travel through portal vein to be recycled by liver
4. 5% of bile salts are lost in feces

Question 4

How do gut microbiota modify bile salts?

Answer 4

A small amount of bile salts will be de-conjugated and modified by microbiota (dehydrogenation, dehydroxylation, epimerization, etc) to produce secondary bile acids
- mainly deoxycholic acid (DCA) and litocholic acid (LCA)

Question 5

How do enterocytes reabsorb bile salts/bile acids on their apical side?

Answer 5

• Bile salt - Via ASBT (apical sodium dependent bile salt transporter)
• Bile acids - Passive diffusion

Question 6

Once bile salts/acids are inside enterocytes what happens?

Answer 6

• Activate FXR (farnesoid X receptor), a nuclear receptor, to produce FGF 19 (fibroblast growth factor 19) - a hormone-like protein, which is secreted out of entercytes and enters portal vein
• Bile salts transported out of enterocyte by transporter and enter portal vein

Question 7

Describe FXR in enterocytes and why it’s important

Answer 7

A nuclear receptor in enterocytes that is activated by bile acids/salts and produces FGF15/19, a hormone-like protein that goes into circulation

Question 8

What happens when bile salts/acids return to liver?

Answer 8

Taken up by heptaocytes via transporters and activate FXR there to produce SHP-1, which inhibits expression of the rate-limiting enzyme for the Classic bile synthesis pathway

• suppresses bile acid generation from cholesterol
• thereby maintaining homeostasis

Question 9

What happens when FGF15/19 reaches liver?

Answer 9

• Acts on hepatocyte and induces intracellular signalling events that can inhibit conversion of cholesterol to bile acids

Question 10

Briefly describe the direct and indirect mechanism of bile acid/salt metabolic regulation

Answer 10

DIRECT - Bile acid-regulated signaling pathways, FXR and TGR5 (transmembrane G-protein-coupled receptor 5)

INDIRECT - FGF15/19 generated by enterocytes

**not limited to liver because bile acid can escape circulation and go anywhere - skeletal muscle, adipose tissue, etc

Question 11

Name two direct effects FXR can have on the body’s metabolism

Answer 11

1. Negatively regulate bile acid pool during synthesis and increase bile acid export
2. Regulate lipid metabolism and gluconeogenesis

Question 12

How does bile acid lower hepatic TAG levels via FXR?

Answer 12

• FXR inhibits SREB-1C (master regulator of de novo lipogenesis) expression by up-regulating SHP-1
• This decreases hepatic TAG synthesis and VLDL secretion

Question 13

How does FXR affect gluconeogenesis in liver?

Answer 13

• Inhibits PEPCK and Glucose-6-phosphatase (two rate-limiting enzymes in glycolysis pathway) via upregulating SHP-1
• Bile acids activate FXR, and therefore suppress gluconeogenesis in liver (alleviating fasting hyperglycemia in liver)

Question 14

Where can TGR5 activation happen? Briefly describe the effects

Answer 14

• SKELETAL MUSCLE and BROWN ADIPOSE TISSUE - activates deiodinase DIO2, which generates T3 (active thyroid hormone)
- increased energy expenditure

• INTESTINAL LUMEN - bile acids activate TGR5 in enteroendocrine cells, resulting in release of incretin GLP-1
- increased insulin secretion and/or sensitivity

• KUPFFER CELLS and MACROPHAGES - TGR 5 activation inhibits LPS-induced cytokine production
- decreased inflammation

Question 15

What are the indirect effects of bile salts on the liver. What plays a role in this?

Answer 15

**Via FGF15/19 production

• Decreased lipogenesis
• Increased glycogen storage
• Decreased gluconeogenesis
• Decreased blie acid synthesis

Question 16

What two metabolic effects will FGF 15/19 production have on any tissue expressing FGF15/19 receptors?

Answer 16

• Increased glucose disposal
• Increased energy expenditure

(eg: brain and adipose tissues)