ADVANCED NUTRITION MACRONUTRIENTS: DIGESTIVE ABSORPTION

Comprehensive vocabulary flashcards covering the biochemical, physiological, hormonal, anatomical, and pharmacological principles of human lipid digestion and absorption across the gastrointestinal tract.

24-Hour Fat Input-Output Balance

In human adults, total daily fat input comprises exogenous dietary lipids ($92\text{--}96\,\text{g}$ triglycerides, $4\text{--}6\,\text{g}$ phospholipids, and $0.5\,\text{g}$ cholesterol) and endogenous sources ($\sim 30\,\text{g}$ bile salts, $10\text{--}15\,\text{g}$ biliary phospholipids, $1\text{--}2\,\text{g}$ biliary cholesterol, $2\text{--}6\,\text{g}$ desquamated cellular membranes, and $\sim 10\,\text{g}$ bacterial membrane lipids). Only $\sim 4\,\text{g}$ of unabsorbed fat is excreted daily in feces, corresponding to an overall absorption efficiency of approximately $97\%$.

Sections of the Stomach

The distinct anatomical regions of the stomach: the cardia (surrounding the esophageal inlet), the fundus (superior dome housing acid-secreting parietal cells and lipase-secreting chief cells), the body (central reservoir), the antrum (distal region regulating motility and gastrin secretion), and the pylorus (muscular sphincter regulating chyme outflow into the duodenum).

Gastric Lipase (GL)

An acid-resistant, protease & HCl-resistant lipase secreted by chief cells in the gastric fundus that undergoes interfacial activation at an acidic optimum pH to cleave triglycerides into free fatty acids and sn-2,3 diacylglycerols, mediating $15\%\text{--}30\%$ of total lipid digestion in adults and an even higher proportion in infants.

Gastric Lipase-Released Fatty Acids

Free fatty acids liberated in the stomach by gastric lipase that function to stabilize the expanding emulsion particles, activate G-protein coupled receptors (GPCRs), stimulate the secretion of GIP, CCK, and secretin, and trigger the downstream activation of pancreatic lipase.

Secretin

A peptide hormone produced by S-cells in the proximal small intestine (duodenum and jejunum) in response to low luminal pH and fatty acids; it stimulates bicarbonate ($\text{HCO}_3^-$) secretion from the liver and pancreatic duct cells while inhibiting gastric $\text{HCl}$ secretion.

Cholecystokinin (CCK)

A peptide hormone secreted by I-cells in the proximal small intestine upon sensing luminal fatty acids; it stimulates gallbladder contraction, induces pancreatic acinar cell digestive enzyme secretion, and promotes bicarbonate output.

Incretins

Gut-derived hormones—specifically Glucose-Dependent Insulinotropic Polypeptide (GIP, from K-cells) and Glucagon-Like Peptide-1 (GLP-1, from L-cells)—stimulated by luminal fatty acids and carbohydrates to potentiate glucose-dependent insulin secretion from the endocrine pancreas.

Glucagon-Like Peptide-1 (GLP-1)

An incretin hormone released by L-cells in the distal small intestine (ileum) in response to fatty acids and carbohydrates; it enhances pancreatic insulin secretion while downregulating gastric $\text{HCl}$ secretion and gastrointestinal motility.

Emulsion Particles

Macromolecular lipid droplets formed mechanically within the stomach comprising a hydrophobic core of nonpolar lipids (predominantly triglycerides and cholesteryl esters) surrounded by an amphipathic surface monolayer of emulsifiers (phospholipids, free fatty acids, and unesterified cholesterol).

Pancreatic Lipase

The major triglyceride-digesting enzyme of the proximal small intestine, synthesized and secreted by pancreatic acinar cells. It requires colipase for interfacial anchoring and specifically cleaves ester bonds at the sn-1 and sn-3 positions of triglycerides to yield two free fatty acids and one sn-2 monoacylglycerol. (important in adults)

Interfacial Activation of Pancreatic Lipase

The conformational opening that occurs when pancreatic lipase binds to a lipid-water interface via its cofactor colipase; colipase interacts with the non-catalytic C-terminus and forms hydrogen bonds that displace an amphipathic surface 'lid' covering the catalytic N-terminus, exposing the active site and $\beta 5$ loop to substrate lipids.

Bile Salt-Activated Lipase

A pancreatic enzyme secreted in an active (non-zymogen) form that strictly depends on bile salts for enzymatic activity; it possesses broad substrate specificity, hydrolyzing ester bonds at sn-1, sn-2, and sn-3 of triglycerides, as well as cholesterol esters and fat-soluble vitamin esters, and plays a prominent digestive role in human milk-fed infants.

Pancreatic Lipase-Related Protein 2 (PLRP2)

A pancreatic lipolytic enzyme that hydrolyzes triglycerides and phospholipids independently of colipase; its expression is particularly high in neonates, collaborating with gastric lipase to digest lipids in breast milk or formula while classical pancreatic lipase levels remain low.

Phospholipase A2 (PLA2)

A lipolytic enzyme secreted by the exocrine pancreas as an inactive zymogen (proPLA2) that hydrolyzes the ester bond at the sn-2 position of phospholipids (predominantly phosphatidylcholine/lecithin), yielding a free fatty acid and a lysophospholipid.

Physical-Chemical Sequence of Lipid Dispersion

The progressive structural breakdown and dispersion of dietary lipids in the proximal small intestine: lipid products bud from core emulsion particles into multilamellar vesicles ($> 1000\,\text{\AA}$), which are disrupted by bile salts (+BS) into unilamellar vesicles ($200\text{--}600\,\text{\AA}$), and finally partitioned into small intestinal mixed micelles ($\sim 50\,\text{\AA}$) for mucosal absorption.

Gallbladder Bile Composition

The concentrated fluid stored in the gallbladder, containing approximately $130\,\text{mM}$ bile acids, $30\,\text{mM}$ phosphatidylcholine, $1\,\text{mM}$ cholesterol, $0.2\,\text{g/dL}$ bilirubin, and $0.3\,\text{g/dL}$ total proteins at a neutral pH of approximately $7$.

Critical Micelle Concentration (CMC)

The threshold concentration of bile salts in aqueous solution—experimentally determined to be $3\text{--}5\,\text{mM}$—required for bile salt monomers to spontaneously aggregate into polymolecular micelles.

Primary Bile Acids

Bile acids synthesized de novo from cholesterol in hepatocytes, comprising cholic acid (CA, hydroxylated at the $3$, $7$, and $12$ positions) and chenodeoxycholic acid (CDCA, hydroxylated at the $3$ and $7$ positions).

Cholesterol 7$\alpha$-Hydroxylase

The initial, rate-limiting enzyme in hepatic bile acid synthesis that converts cholesterol into 7$\alpha$-hydroxycholesterol; its activity is down-regulated via negative feedback inhibition by circulating bile acids.

Bile Salt Synthesis Pathway

The metabolic pathway in the liver converting cholesterol into primary bile acids via 7$\alpha$-hydroxylase, subsequent conjugation with taurine or glycine in a $1:3$ ratio, and downstream conversion by microbial deconjugation and 7$\alpha$-dehydroxylation into secondary bile acids (deoxycholic acid and lithocholic acid) in the intestinal lumen.

Secondary Bile Acids

Bile acids produced in the intestine when colonic bacteria enzymatically deconjugate and 7$\alpha$-dehydroxylate primary bile acids, converting cholic acid into deoxycholic acid (DCA) and chenodeoxycholic acid into lithocholic acid (LCA).

Bile Salt Conjugation

The hepatic covalent addition of taurine or glycine to primary bile acids, which lowers their intrinsic $\text{p}K_a$ (e.g., from $\text{p}K_a \approx 6$ for cholate to $\text{p}K_a \approx 4$ for glycocholate), ensuring full ionization ($\text{COO}^-$) at jejunal pH ($\approx 6$) and dramatically enhancing lipid-solubilizing capacity.

Enterohepatic Circulation of Bile Salts

The recycling pathway whereby a total bile salt pool of $2\text{--}4\,\text{g}$ is secreted into the intestine at a rate of $15\text{--}30\,\text{g/day}$, actively reabsorbed in the terminal ileum, and returned via the portal vein to the liver $8\text{--}10\times/\text{day}$, with daily fecal excretion limited to $\sim 0.5\,\text{g/day}$ matched by hepatic de novo synthesis.

Apical Sodium-Dependent Bile Acid Transporter (ASBT / IBAT)

An active sodium-dependent symporter located on the brush border membrane of distal ileal enterocytes responsible for reclaiming conjugated and unconjugated bile acids from the intestinal lumen into the enterohepatic circulation.

Fatty Acid-Binding Proteins (FABPs)

Intracellular chaperone proteins in enterocytes; I-FABP mediates rapid, targeted delivery of absorbed free fatty acids to the endoplasmic reticulum membrane, whereas L-FABP facilitates slower cytosolic diffusion of both fatty acids and monoacylglycerols.

Long-Chain Acyl-CoA Synthetase (ACS)

An endoplasmic reticulum-associated enzyme that catalyzes the ATP-dependent activation of absorbed free fatty acids by conjugating them to coenzyme A ($\text{FA} + \text{CoA} \rightarrow \text{Fatty acyl-CoA}$), preparing them for downstream re-esterification pathways.

Pathways of Lipid Esterification in the Intestine

The biochemical mechanisms for triglyceride resynthesis in enterocytes: the predominant Monoacylglycerol Acyltransferase (MGAT) pathway (converting 2-monoacylglycerol sequentially to diacylglycerol and triacylglycerol via MGAT and DGAT) and the minor Glycerol-3-Phosphate Acyltransferase (GPAT) pathway (utilizing glycerol-3-phosphate from glycolysis or liver glycerol kinase).

Microsomal Triglyceride Transfer Protein (MTP / MTTP)

An essential endoplasmic reticulum chaperone that transfers newly synthesized neutral lipids (triglycerides and cholesteryl esters) onto nascent apolipoprotein B-48 (ApoB48) during the assembly of primordial chylomicrons in enterocytes.

Chylomicron (CM)

A large, triacylglycerol-rich lipoprotein assembled in enterocytes containing a core of triglycerides and cholesteryl esters surrounded by ApoB48, phospholipids, and cholesterol; it exits the basolateral membrane in pre-chylomicron transport vesicles (PCTVs) and enters mesenteric lacteals.

Intestinal Villus Lacteal

A specialized central, blind-ended lymphatic vessel within each intestinal villus, lined with lymphatic endothelial cells (stained with LYVE-1, red) and bordered by enterocyte nuclei (stained with DAPI, blue), that takes up exocytosed chylomicrons for transport through mesenteric lymphatics into systemic circulation.

Niemann-Pick C1-Like 1 (NPC1L1)

A polytopic transmembrane sterol transporter situated at the brush border membrane of jejunal enterocytes that mediates the active uptake of luminal dietary and biliary cholesterol as well as non-cholesterol plant sterols.

ATP-Binding Cassette Transporters G5 and G8 (ABCG5/G8)

An apical obligate heterodimeric efflux pump in enterocytes and hepatocytes that actively expels unesterified cholesterol and non-cholesterol plant sterols back into the intestinal lumen or bile duct, preventing toxic phytosterol accumulation.

Acyl-CoA:Cholesterol Acyltransferase 2 (ACAT2)

An intracellular enzyme in enterocytes that catalyzes the esterification of absorbed free cholesterol with fatty acyl-CoA to form cholesteryl esters, allowing their packaging into the core of nascent chylomicrons.

Trans-Intestinal Cholesterol Excretion (TICE)

A non-biliary pathway for cholesterol elimination in which circulating plasma-derived cholesterol is extracted across the basolateral membrane of enterocytes and directly secreted into the intestinal lumen for fecal excretion.

Phytosterols

Plant-derived sterols and stanols (primarily sitosterol with an absorption rate of $\sim 0.5\%$\text{ and sitostanol with an absorption rate of }$\sim 0.05\%$) that compete with cholesterol (absorption rate $\sim 50\%$) for micellar solubilization; sustained daily consumption of $2\text{--}3\,\text{g}$ lowers serum LDL cholesterol by $8\%\text{--}10\%$.

Orlistat (Tetrahydrolipstatin)

A saturated derivative of lipstatin produced by Streptomyces toxytricini (marketed as Xenical and Alli) that acts as an irreversible active-site inhibitor of gastric and pancreatic lipases, blocking intestinal triglyceride hydrolysis and absorption, with side effects including steatorrhea and fat-soluble vitamin malabsorption.

Ezetimibe

A pharmacological drug (marketed as Zetia) prescribed for hypercholesterolemia that specifically inhibits the NPC1L1 sterol transporter at the enterocyte brush border, blocking the intestinal uptake of dietary cholesterol, biliary cholesterol, and plant sterols.

(helps produce “chyme,” a mixture containing lipid emulsions)

Mechanical action of the stomach?

HCl Secretion

What type of secretion does the stomach do thanks to parietal cells in fundus

PL, FA, cholesterol

Examples of emulsifiers (surface lipids) in the stomach?

Chyme

passes emulsions from the stomach to the SI

The exocrine pancreas

secreting specialized fat-splitting enzymes and alkaline fluid directly into the small intestine.

Zymogen

pro-enzyme

LIPID DIGESTION

Breaking down the dietary fats in the lumen of the GI tract

• Hormonal regulation

• Hydrolysis (breakdown) of dietary

lipids by lipases

• Importance of bile acids for

solubilizing dietary lipids so they

can be digested & then absorbed

LIPID ABSORPTION

Taking up the products of digestion into the intestinal epithelial cells

• Uptake of the hydrolysis products

of lipid digestion

• Intracellular lipid metabolism

• Formation of lipoproteins

• Secretion of the lipids (packaged

into lipoproteins) from the

intestine, for delivery to the rest of

the body.

They are combined two FA and a MG underneath to form a triglyceride, which in turn forms a chylomicron that can be sent out the the lympathic system

When FA and MG are absorbed in the proximal intestinal enterocyte, what happens?

CD36,FATP4

Fatty acid carrier protein

I-FABP

rapid delivery of FA to ER membrane

L-FABP

lower diffusion of FA, MAGs to ER

Plant Sterols

• Structure and absorption

• Food sources

• Benefits

• An average phytosterol intake of 2-3 g/day

lowers serum LDL-cholesterol by 8%-10%;

continuous intake

• Average intake is 300 mg/d- 600 mg/d

• Recommended by AHA, FDA Health claim

excretion

• Chol can be excreted in feces

• Lowers total body pool of cholesterol

• Biliary route

• TICE (trans-intestinal cholesterol excretion

List some fecal cholesterol sources

MTP, microsomal TG transfer protein

transfers TG to ApoB48

ApoB48

TG from ER → Golgi PCTV: pre-CM transport vesicle CM: chylomicron

MGAT pathway

predominant in enterocyte with the breakdown of monoacylglyceral to diacylglycerol

GPAT pathway

Breakdown of glycerl 3 phosphate to phosphatidate

Gherlin

Increases food intake

130 Mm with 10-15% of total solids. Major functions of bile are being able to emulsify lipids that helps breaks down large fat globules into tiny droplets (increases surface area)

What is the approximate composition of gall bladder bile? Major functions of bile?

Gastric Inhibitory Polypeptide (GIP)

High insulin secretion from pancreas(secreted by proximal small intestine K cells) that decreases HCl secretion and motility