Ch11: Lipid and Amino Acid Metabolism

Dietary Fats

Triacylglycerols, cholesterol, cholesteryl esters, phospholipids, FFA

Lipid Digestion: Mouth and Stomach

Mechanical digestion

Lipid Digestion: Duodenum

Emulsification by bile to increase SA for enzyme interactions

Lipid Digestion: Pancreatic Enzymes

Pancreatic lipase, colipase, cholesterol esterase

Hydrolyze lipids to 2-monoacylglycerol, FFA, and cholesterol

Lipid Absorption: Micelles

Water-soluble exterior with lipid-soluble interior

Composed of FFA, cholesterol, 2-monoacylglycerol, and bile salts

Transport lipids into small intestine mucosal cells

Micelles: Bile Salts

Reabsorbed in ileum

Lipid Absorption: Chylomicrons

Package triacylglycerols and cholesteryl esters reformed from digested lipids

Leave intestine via lacteals and enter bloodstream via thoracic duct

Lipid Absorption: Short-Chain FA

Water-soluble

Diffuse into bloodstream

Lipid Mobilization: Hormone-Sensitive Lipase (HSL)

Activated by decreased insulin or increased epinephrine and cortisol

Release from adipose tissue

Hydrolyze triacylglycerols → FA + Glycerol (glycolysis or gluconeogenesis)

Lipid Mobilization: Lipoprotein Lipase (LPL)

Metabolize chylomicrons

Release FFA from triacylglycerols in VLDL

Lipid Transport: Albumin

Transport FFA

Lipid Transport: Lipoproteins

Apolipoprotein and lipid complex

Transport triacylglycerol and cholesterol

Lipoprotein: Density

Chylomicron: Least dense (highest fat:protein)

VLDL

IDL

LDL

HDL: Highest density

Transport: Chylomicrons and VLDL

Primarily carry triacylglycerols with some cholesteryl esters

Transport: IDL

Transition between VLDL and LDL

Primary lipid from triacylglycerol → cholesterol

Transport: LDL and HDL

Primarily carry cholesterol

Chylomicrons

Soluble in lymphatic fluid and blood

Transport triacylglycerol, cholesterol, cholesteryl ester

Assemble in intestinal lining

VLDL

Transport triacylgylcerol to tissues

Produce and assemble in liver

IDL

Produce from triacylglycerol removal from VLDL

Reabsorb by liver or further processing to LDL in bloodstream

Transport cholesteryl esters from HDL

LDL

Transport cholesterol to tissues

Produce from IDL

HDL

Contain apolipoproteins for cholesterol cleaning from blood (“good” cholesterol)

Transport apolipoproteins to lipoproteins and cholesterol to tissues

Synthesize in liver and intestines

Apolipoproteins/Apoproteins

Protein component of lipoprotein

Receptor molecules for signalling

Cholesterol Functions

Cell membrane, steroid hormone, bile acid, and vit D synthesis

Cholesterol Sources

LDL and HDL

De novo synthesis

Cholesterol: De novo Synthesis Location

In hepatic cell cytoplasm

De novo Synthesis: Citrate Shuttle

Carry mitochondrial acetyl-CoA into cytoplasm

De novo Synthesis: HMG-CoA Reductase

Synthesize mevalonic acid in smooth ER

Rate-limiting step

Cholesterol Synthesis: Regulation

Inhibition: Increased cholesterol (neg feedback)

Activation: Increase insulin

Cholesterol Transport: Lecithin-Cholesterol Acyltransferase (LCAT)

Activated by HDL apoproteins

Add FA to cholesterol → Cholesteryl ester to lipoproteins

Cholesterol Transport: Cholesteryl Ester Transfer Protein (CETP)

Facilitate cholesteryl ester transfer from HDL to IDL (form LDL)

FA Nomenclature

\# C:# double bonds

FA Nomenclature: Omega Numbering System

For unsaturated FA

Identify last double bond relative to chain end and major precursor FA

\# C:# double bonds cis/trans-double bond positions

Omega Numbering System: Precursor FA

\# C - Last double bond

Saturated FA

No double bonds

Unsaturated FA

Double bonds

Most synthesized from diet essential FA

Important Essential FA

a-linolenic acid and linoleic acid → Maintain cell membrane fluidity

FA Synthesis

Diet FA

Excess diet carb and protein convert to FA

FA Biosynthesis

In liver

Stimulated by insulin

Product: Palmitic acid (palmitate) → Adipose for storage

FA Biosynthesis: Acetyl-CoA Shuttling

Fed state slows TCA and causes citrate accumulation

Citrate lyase in cytosol cleave citrate into acetyl-CoA and oxaloacetate

FA Biosynthesis: Acetyl-CoA Carboxylase

Acetyl-CoA + CO2 → Malonyl-CoA activation

Rate-limiting enzyme

Activation: Insulin, citrate

FA Biosynthesis: FA (Palmitate) Synthase

Activation, bond formation, reduction, dehydration, reduction x8 → Palmitate

Require pantothenic acid (vit B5) and NADPH

Activation: Insulin

Triacylglycerol Synthesis

Attach 3 FA to glycerol 3-P in liver and adipose

Liver triacylglycerol sent to adipose as VLDL

Beta/β-Oxidation

FA catabolism in mitochondria

Oxidation, hydration, oxidation, cleavage

Stimulated by glucagon

Inhibited by insulin

Alpha-Oxidation

Branched FA catabolism (depend on branch points)

Omega-Oxidation

In ER

Produce dicarboxylic acids

β-Oxidation: Fatty-Acyl-CoA Synthetase

FA attach to CoA → Acyl-CoA

β-Oxidation: FA Into Mitochondria

Short-chain (2-4 C) and medium-chain (6-12 C) FA diffuse freely

Long-chain (14-20 C) FA use carnitine acyltransferase I (rate-limiting enzyme)

β-Oxidation: In Mitochondria

Oxidize and release acetyl-CoA

Muscle and Adipose: Acetyl-CoA into TCA

Liver: Acetyl-CoA activate pyruvate carboxylase for gluconeogenesis, ketone body synthesis

β-Oxidation: Even-Numbered FA

Final cycle yields 2 acetyl-CoA (2 C)

β-Oxidation: Odd-Numbered FA

Final cycle yields 1 acetyl-CoA + 1 propionyl-CoA

Exception to “FA cannot convert to glucose” rule

Propionyl-CoA Carboxylase

Convert propionyl-CoA → Methylmalonyl-CoA

Methylmalonyl-CoA Mutase

Convert methylmalonyl-CoA → Succinyl-CoA (TCA) → Malate (gluconeogenesis)

β-Oxidation: Monounsaturated FA

Enoyl-CoA isomerase move cis C3=C4 to trans C2=C3

β-Oxidation: Polyunsaturated FA

2,4-dienoyl-CoA reductase convert 2 conjugated C=C to 1 double bond at C3=C4 → Same rearrangement as monounsaturated FA

Ketone Bodies

Excess acetyl-CoA in liver from β-oxidation during fasting state

Acetoacetate and 3-hydroxybutyrate

Ketone Bodies: Metabolism

Cardiac and skeletal muscle

Renal cortex

Brain

Ketogenesis Location

In hepatic mitochondria

Ketogenesis: HMG-CoA Synthase

Acetyl-CoA → HMG-CoA

Ketogenesis: HMG-CoA Lyase

HMG-CoA → Acetoacetate reduce → 3-hydroxybutyrate

Ketolysis: Location

In non-hepatic mitochondria

Ketolysis: Succinyl-CoA Acetoacetyl-CoA Transferase (Thiophorase)

Acetoacetate oxidize → Acetoacetyl-CoA

Ketolysis in Brain

Inhibit pyruvate dehydrogenase

Decrease glycolysis and glucose uptake to prevent protein breakdown

Protein Catabolism

Rare unless extreme need

In muscle and liver

Protein Catabolism: Trans/deamination

Remove amino acid amino group → Ammonia

C skeleton for energy

Protein Catabolism: Gluconeogenesis

Produce energy from glucogenic amino acid C skeletons and non-basic side chains

Protein Catabolism: Ketogenesis

Produce energy from ketogenic amino acid C skeletons and non-basic side chains

Protein Catabolism: Urea Cycle

Liver remove ammonia and basic side chains