LIPID DIGESTION

Anson Lowe

October 02, 2015

Understand the digestion of lipids from the mouth to the bloodstream

Cholesterol absorption

Triglycerides; cholesterol; absorption

Lipids

Elephant seal milk - 55% fatHalf and half - 10% fatHuman breast milk - 5% fat

Birthweight = 60 lbs.30 days old = 250 lbs.

USGS

speed = 60-100 mphdistance 20,000 miles

Migrates 25,000 miles/yearNon-stop 2,400 miles

Ruby-Throated Hummingbird

Migrates across the Gulf of Mexico - 500 mi Time ~ 10-20 hrs Speed = 50 mi/hr Bird weight 3-4 grams (little more than a penny) O2 consumption: 250 ml/hr Power = (0.25 L O2/hr)(4.82 kcal/liter O2) =1.2 kcal/hr or 12 kcal for a 10hr trip Fat required = 12kcal, 9kcal/gm=1.3 gm Fuel weight if carbohydrates used 4kcal/gm = 3.0 gm

Oliver Pearson. The metabolism of hummingbirds. Scientific American, January, 1953, p. 69-72.

Lipid Source

Source

Diet 75%

Bile 10%

Sloughed Cells 15%

Dietary Source

Triglycerides make up 95% of dietary lipids

Cholesterol

Stryer, Biochemistry, 5th ed.

Phospholipids

Salivary Glands and Stomach

Initiation of lipid digestion with salivary and gastric lipase◦Results in the liberation of some free fatty acids,

which stimulates CCK and secretin secretion.Mixing and emulsifying lipids into small

droplets.

Duodenum

CCK and Secretin results in the secretion of bile and pancreatic secretions into the intestine.

Bile Salts incorporate triglycerides and cholesterol into micelles.

Pancreatic Lipase/Colipase

Lipase cleaves the 1and 3 fatty acyl chains off of triglyceride◦Colipase facilitates triglyceride hydrolysis by keeping

lipase at the interface with the lipid droplet◦Colipase is activated by trypsin

Orlistat

Used for the treatment of obesityCovalently binds to a serine in the active site of

gastric and pancreatic lipaseCauses fat malabsorptionAdverse effects

06/07/2007PAL Announces First Bitter Pill Award of 2007 to GlaxoSmithKline: 'With Allies Like This, Who Needs Enemas?’ Award

Bile salt-dependent lipase

Produced in the pancreas and mammary glandCleaves carboxy-ester bond of triglycerides and

cholesterol esters◦Can completely hydrolyze triglycerides to glycerol

and fatty acids◦ Is an important source for lipase in neonates with

immature pancreatic function.

Unstirred Water Layer

Long chain fatty acid absorption Previously thought that long chain (C>12) were only passively absorbed

by the intestine. A series of protein transporters have been described that transport fatty

acids into cells (FATP).◦ FATP4 is highly expressed in the intestine◦ A knockout for FATP4 is lethal◦ Heterozygotes for FATP4 mutation have decreased fatty acid absorption

Dietary Lipid Uptake

Fatty Acid Binding Protein

Isoforms are present in many cells (liver, muscle and intestine)

FABP2 is highly expressed in the intestine◦Cytosolic carrier for long chain fatty acids

Apolipoprotein B

240 kDa proteinforms amphipathic spherical shell around the

fat globule◦solubilizes hydrophobic lipids◦contains cell targeting signals

Sci Rep. 2011;1:139

Dietary Lipid Uptake

http://www.elu.sgul.ac.uk/rehash/guest/scorm/294/package/content/liver_lipoprotein.html

Abetalipoproteinemia

Mutations in microsomal triglyceride transfer protein (MTP)◦Failure to thrive, fat malabsorption, retinal

pigmentation, coagulation disordersPathology reveal enterocyte engorgement with

lipid.

Sidler: Arch Pediatr Adolesc Med, 151(12):1265-1266

Abetalipoproteinemia-Therapy

Administration of medium chain triglycerides (C6-C12).◦Are more water soluble than long chain FAs◦Can be absorbed into enterocytes without bile acids◦ Incorporation into chylomicrons is not necessary

Is released directly into the portal circulation

Sterol Absorption

Animal derived sterols (cholesterol) are preferentially absorbed over plant sterols (sitosterol, brassicasterol, and avanesterol)

A specific protein, has been found that specifically transports cholesterol

NPC1L1

Gene was found via a genomics-bioinformatics approach◦ signal peptide◦ transmembrane domain◦N-glycosylation site◦ cholesterol interacting site/sterol sensing domain

Resulted in one candidate gene

Altmann et al. Science, Vol 303, 1201-1204 (2004)

Altmann et al. Science, Vol 303, 1201-1204 (2004)

Altmann et al. Science, Vol 303, 1201-1204 (2004)

J.W. Clader, J. Med. Chem., 47, 1 -9 (2004)

Sterol Efflux Animal derived sterols (cholesterol) are preferentially absorbed over

plant sterols (sitosterol, brassicasterol, and avanesterol) ABCG5 and ABCG8 form a heterodimer and are responsible for intestinal

efflux and hepatocyte excretion of cholesterol.◦ Responsible for cholesterol secretion into the bile caniliculus

Small, D.M., PNAS (2003) 100:4-6

J. Clin. Invest. 110 :671-680 (2002)

Malabsorption

Loss of lumenal digestion(effects on pancreatic enzymes)◦chronic pancreatitis◦blocked pancreatic duct◦absence of bile salts◦wrong pH

MalabsorptionLoss of mucosal absorption

(Loss of mucosal surface)◦ celiac sprue

autoimmune process initiated by gliadin derived from glutin◦whipple disease

Tropheryma whippelii◦ tropical sprue◦Crohn’s disease

Celiac Sprue

Small Intestine Surface Area

Normal ~300 m2

Tube 2 cm in diameter and 4 meters long~.25 m2

MalabsorptionLoss of mucosal digestion and absorption

(Loss of mucosal surface)◦ celiac sprue

autoimmune process initiated by gliadin derived from glutin◦whipple disease

Tropheryma whippelii◦ tropical sprue◦Crohn’s disease

Malabsorption

Loss of mucosal digestion(Loss of enzymatic activity or transport)◦ lactose intolerance