October 02 2015 Understand the digestion of lipids from the mouth to the bloodstream Cholesterol absorption Triglycerides cholesterol absorption Lipids Elephant seal milk 55 fat Half and half 10 fat ID: 929716
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Slide1
Lipid Digestion
Anson Lowe
October
02, 2015
Slide2Understand the digestion of lipids from the mouth to the bloodstream
Cholesterol absorption
Triglycerides; cholesterol; absorption
Slide3Lipids
Slide4Slide5Elephant seal milk - 55% fat
Half and half - 10% fat
Human breast milk - 5% fat
Birthweight
= 60 lbs.
30 days old = 250 lbs.
Slide6USGS
speed = 60-100 mph
distance 20,000 miles
Migrates 25,000 miles/year
Non-stop 2,400 miles
Slide7Ruby-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.
Slide8Lipid Source
Source
Diet
75%
Bile
10%
Sloughed Cells
15%
Slide9Dietary Source
Triglycerides make up 95% of dietary lipids
Slide10Cholesterol
Stryer, Biochemistry, 5th ed.
Slide11Phospholipids
Slide12Salivary 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.
Slide13Duodenum
CCK and Secretin results in the secretion of bile and pancreatic secretions into the intestine.
Bile Salts incorporate triglycerides and cholesterol into micelles.
Slide14Slide15Slide16Slide17Slide18Slide19Slide20Pancreatic 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
Slide21Slide22Orlistat
Used for the treatment of obesity
Covalently binds to a serine in the active site of gastric and pancreatic lipase
Causes fat malabsorption
Adverse effects
Slide2306/07/2007
PAL Announces First Bitter Pill Award of 2007 to GlaxoSmithKline: 'With Allies Like This, Who Needs Enemas?’ Award
Slide24Bile salt-dependent lipase
Produced in the pancreas and mammary gland
Cleaves 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.
Slide25Unstirred Water Layer
Slide26Slide27Long 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
Slide28Slide29Slide30Slide31Slide32Dietary Lipid Uptake
Slide33Fatty 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
Slide34Slide35Slide36Apolipoprotein
B
240 kDa protein
forms amphipathic spherical shell around the fat globule
solubilizes hydrophobic lipids
contains cell targeting signals
Slide37Slide38Slide39Sci Rep.
2011;1:139
Slide40Dietary Lipid Uptake
Slide41http://
www.elu.sgul.ac.uk
/rehash/guest/
scorm
/294/package/content/
liver_lipoprotein.html
Slide42Abetalipoproteinemia
Mutations in
microsomal
triglyceride transfer protein (
MTP
)
Failure to thrive, fat
malabsorption
, retinal pigmentation, coagulation
disorders
Pathology reveal
enterocyte
engorgement with lipid.
Slide43Slide44Sidler:
Arch Pediatr Adolesc Med
, 151(12):1265-1266
Slide45Abetalipoproteinemia
-Therapy
Administration of
medium chain triglycerides
(C
6
-C
12
).
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
Slide46Sterol 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
Slide47NPC1L1
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
Slide48Altmann et al.
Science
, Vol 303, 1201-1204 (2004)
Slide49Altmann et al.
Science
, Vol 303, 1201-1204 (2004)
Slide50Altmann et al.
Science, Vol 303, 1201-1204 (2004)
Slide51J.W. Clader,
J. Med. Chem.,
47, 1 -9 (2004)
Slide52Sterol 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
Slide53Small, D.M.,
PNAS
(2003) 100:4-6
Slide54J. Clin. Invest.
110
:671-680 (2002)
Slide55Malabsorption
Loss of
lumenal
digestion
(effects on pancreatic enzymes)
chronic pancreatitis
blocked pancreatic duct
absence of bile salts
wrong pH
Slide56Malabsorption
Loss of
mucosal
absorption
(Loss of mucosal surface)
celiac
sprue
autoimmune process initiated by
gliadin
derived from
glutin
whipple
disease
Tropheryma
whippelii
tropical
sprueCrohn’s disease
Slide57Celiac Sprue
Slide58Small Intestine Surface Area
Normal ~300 m
2
Tube 2 cm in diameter and 4 meters long
~.25 m
2
Slide59Malabsorption
Loss 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
Slide60Malabsorption
Loss of mucosal digestion
(Loss of enzymatic activity or transport)
lactose intolerance