152. Bile Salts + Lipid Absorption

Question 1

How are fats digested in gastric and pancreatic phase?

Answer 1

Gastric: lipase converts TG to 1 DAG and 1 FFA
Pancreatic: lipase stim by TG binding duodenal cells = CCK release = pancreatic secretion
converts TG to 1 MAG and 2 FFA

Question 2

What is bile composed of?
How are they exported from the liver?
Where does bile from the liver go?
What is the function of the gallbladder?
How does bile help absorb lipids?

Answer 2

Bile: bile salts (amphipathic, spontaneous micelle formation), cholesterol, phospholipids, bilirubin
Hepatic Exports: ABCG5/8 for cholesterol; BSEP for bile salts
Secretions: 50% duodenum, 50% gallbladder - depends on relative tone of sphincter of Oddi (fasting = more to gallbaldder)
Gallbladder: expands as fills with bile during fasting, concentrates and acidifies bile, contracts by CCK stim to secrete more bile to duodenum

formation of mixed micelles in duodenum = how bile salts enhance lipid solubility = solubilizes bile salts, cholesterol, phospholipids, MAG, LCFAs (SCFA/MCFA do not need micelle formation for absorption)

Question 3

How are SCFA, MCFA, and LCFA taken up by intestine?

Answer 3

Mixed micelles: facilitate transport of lipids to enterocyte brush border membrane - lipids leave micelle into enterocyte via passive diffusion and active transport (LCFA)

SCFA/MCFA: absorbed via passive diffusion, go direct to portal circulation

LCFA: in enterocyte, RE-ESTERIFIED with MAG to form TG - assemble with cholesterol, phospholipids, apolipoproteins to form CHYLOMICRONS - transferred by exocytosis to lacteals = lymphatics = bloodstream thru lymphatic duct

Question 4

Describe the enterohepatic circulation of bile acids

Answer 4

Bile acids release lipid content and travel to DISTAL ILEUM
Distal Ileum: active bile salt absorption via ASBT (Na-dependent) - enters portal circulation from enterocyte via OSTa/b membrane transporter
Liver: return to liver from portal vein, taken up via NTCP (efficient uptake prevents bile entry to systemic circulation)

EHC: recirculates 4-12x/day (5x/fatty meal); 95% reabsorbed each cycle, 5% excreted fecally - matched by new bile acid synthesis

Question 5

How are bile acids synthesized?

Describe the feedback mechanisms for bile acid synthesis.

What is the effect of bile acid sequestrants?

Answer 5

Made in liver from cholesterol: rate limiting step is CYP7A1, then conjugated to make bile salts (more potent detergents)

Feedback:
- less bile acid return to liver = stim CYP7A1 = more synthesis
- more bile acid return to liver = inhibit CYP7A1 = less synthesis
- FXR: nuclear receptor binding bile acids in liver (binding = more SHP transcription factor = inhibit CYP7A1 = less bile acid synthesis) and enterocyte (binding = more FGF19 = binds FGFR4 in liver = inhibits CYP7A1 = less synthesis)
FXR and FGFR4 have role in glucose metabolism (DM), Lipid metabolism (Fatty Liver Disease), Cholestatic liver disease

Bile Acid Sequestrants
- less bile recycled = stim CYP7A1 = more bile acid synthesis = more metabolism of cholesterol = lower cholesterol

Question 6

What are the two causes of fat malabsorption?

Answer 6

Bile Acid Deficiency: Chronic cholestasis (PBC) causing poor bile acid secretion and Ileal Resection (Crohn’s Disease) causing poor bile acid reabsorption

Exocrine Pancreas Insufficiency: chronic pancreatitis (alcohol)

Question 7

What are the risk factors for cholelithiasis?

What are the 2 broad causes of cholestasis and the consequences?

Answer 7

RF: cholesterol supersaturation due to high cholesterol secretion or low bile acid secretion; gallbladder stasis (due to prolonged fasting, pregnancy, TPN); high mucin production (CF); hydrophobicity of bile

Cholestasis

1. Intrahepatic impaired bile flow = less bile acid secretions from hepatocytes into bile canaliculi
2. Extrahepatic impaired bile flow = blockage of extrahepatic bile ducts (gallstones, strictures, cancers)

Consequences: Liver Toxicity (excess bile acid causes inflammation in hepatocytes), Spillover of compounds in enterohepatic circulation into systemic circulation (Bile acids = pruritis, bilirubin = jaundice), Fat malabsorption