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Digestion of Triacylglycerols

Luminal digestion (small intestine)

  • lipase hydrolyzes fatty acids from C1 and C3 in the lumen

  • bile salts (derived from cholesterol):

  • made in the liver

  • secreted into the lumen
  • supported by colipase

Products

  • product is 2-monoacylglycerol (2MG)
  • when enclosed with bile salt, it is called a micelle
  • bile salts remain in the lumen
  • fatty acids + 2MG are absorbed

Re-esterification inside cells (re-forming TAG)

  • absorbed fatty acids and 2MG are converted back into triacylglycerol (TAG) (too big to transport as free lipids)

Steps :

  1. 2MG is activated with FA1CoA into a higher energy state (C1 with R1; CoA-SH leaves) → forms diacylglycerol
  2. repeats → forms triacylglycerol

Packaging: lipoproteins

Lipoproteins package:

  • triacylglycerols
  • cholesterol

They include :

  • protein, phospholipids, free cholesterol surrounding triacylglycerols

Why apoproteins matter

  • water solubility
  • stability
  • functionality
  • activate enzymes
  • act as ligands for target cells

Lipoprotein types (more dense → less dense)

Key rule:

  • more protein = more dense
  • more lipid = less dense

Chylomicrons (Apo B-48)

  • Apo B-48

  • mature chylomicrons have :

  • Apo C-II (activator for lipoprotein lipase; needed in muscle and fat)

  • Apo E for maturity
  • Apo C-II and Apo E are picked up from HDL

Route and processing

  • intestine → lymphatic system → blood
  • interaction: lipoprotein lipase + Apo C-II

Fates :

  • Apo C-II returns to HDL
  • Apo B-48 and Apo E back to liver
  • fatty acids stay (delivered to tissues)
  • glycerol goes to liver (gluconeogenesis / glycolysis)

Key label:

  • intestine to tissues = exogenous

VLDL (Apo B-100)

  • Apo B-100
  • acquires Apo C-II and Apo E from HDL for maturity

Route and processing

  • lymphatic system → blood → lipoprotein lipase + Apo C-II interaction

  • after delivering ~50% lipid contents:

  • remnants (glycerol to liver)

  • remaining becomes IDL

Key label:

  • endogenous (fat built inside cells)

IDL (subtype of VLDL)

  • IDL interacts with HTGL and gives more lipid contents, then becomes LDL

LDL (subtype of IDL) — “lower is better”

  • ~60% removed by liver
  • ~40% delivers cholesterol content to other cells

If receptors are saturated :

  • LDL engulfed by macrophages
  • inflammation increases
  • LDL drops cholesterol contents

Other note :

  • oxidized easily if in epithelial layer

HDL (Apo A-1) — “higher is better”

  • Apo A-1
  • collects cholesterol from non-liver tissue and releases into liver
  • reverse cholesterol transport

Cholesterol loading and unloading

  • other cells use ABCA1 (ATP-binding cassette transporter 1) to flip cholesterol outward and present it to HDL
  • HDL acquires cholesterol with LCAT (lecithin cholesterol acyltransferase)
  • liver removes HDL cholesterol via scavenger receptor B1

Other effects :

  • can secrete nitric oxide
  • dilates blood vessels

Familial hypercholesterolemia (FH)

  • autosomal dominant

Heterozygous

  • ~2× higher cholesterol
  • skin deposits: xanthoma

Homozygous

  • heart attack before age 20
  • death before age 20

Fatty acid synthesis

Occurs mostly in liver, may also occur in adipose tissue.

Citrate shuttle and malonyl-CoA formation

  • acetyl-CoA → citrate → leaves mitochondrial matrix (in exchange for pyruvate)
  • citrate lyase (uses ATP) converts citrate → acetyl-CoA + oxaloacetate
  • acetyl-CoA → malonyl-CoA

Palmitate production

  • fatty acid synthase + NADPH → NADP\(^+\)
  • produces palmitate
  • then converted into FA-CoA
  • then forms TAG and leaves

OAA → malate → pyruvate (NADPH generation)

  • oxaloacetate → malate via cytosolic malate dehydrogenase (NADH → NAD\(^+\))
  • malate → pyruvate using NADP\(^+\) → NADPH, releasing CO\(_2\)

Acetyl-CoA carboxylase (ACC)

Reaction :

  • acetyl-CoA + ATP + CO\(_2\) → malonyl-CoA

Regulation :

  • citrate activates ACC (to make it conjugated)
  • palmitoyl-CoA inhibits ACC (to make it not conjugated)
  • ACC is active if not phosphorylated
  • AMPK inactivates ACC by phosphorylation

Fatty acid synthase (FAS)

  • 2 subunits (head-to-tail configuration)
  • 7 functions

Acyl carrier protein (ACP)

  • ACP has a phosphopantetheine residue (–SH) that binds the growing fatty acid

FAS cycle

  1. acetyl from acetyl-CoA binds to ACP of FAS, then transfers to the tail of unit 2
  2. malonyl from malonyl-CoA binds to ACP of FAS
  3. acetyl on tail of unit 2 merges onto malonyl via ketoacyl synthase with release of CO\(_2\) → forms \(\beta\)-keto-acyl group
  4. reduce \(\beta\)-keto-acyl group via ketoacyl reductase (uses NADPH)
  5. dehydration via hydratase (forms a double bond)
  6. enoyl reductase converts that double bond into a single bond
  7. move the growing chain onto the tail of unit 2
  8. malonyl binds again and cycle repeats

Termination :

  • repeats until 16 carbons, then cuts
  • 7 rounds total

Synthesis of triacylglycerol (TAG)

Glycerol-3-phosphate production

Liver :

  • glycerol + ATP via glycerol kinase → glycerol-3-phosphate

Liver and adipose tissue :

  • glucose → DHAP → glycerol-3-phosphate

Building TAG

  • glycerol-3-phosphate + FA–CoA

  • forms phosphatidic acid:

  • C1 and C2 esterified with FA

  • C3 has phosphate
  • phosphate leaves
  • another FA–CoA joins → forms TAG

Fate :

  • TAG either stored as adipose or packaged into VLDL