Lipids and Lipoproteins: Structure, Function, and Metabolism

Lipids

A diverse and vital group of molecules fundamental to human nutrition and metabolic health.

Triacylglycerols (Triglycerides)

The most abundant class of lipids in the diet and the body, serving as a highly concentrated form of stored energy.

Phospholipids

Critical structural components of cell membranes, characterized by their amphipathic nature.

Sphingolipids

Built upon a sphingosine backbone rather than glycerol, including compounds like ceramides, sphingomyelins, and cerebrosides.

Sterols

Characterized by a four-ring steroid nucleus, vital for membrane structure and as precursors for other critical molecules.

Cholesterol

The most common sterol in humans, serving as the parent compound for bile acids and all steroid hormones.

Phytosterols

Sterols synthesized by plants that can interfere with cholesterol absorption in the human intestine.

Essential Fatty Acids

Fatty acids that cannot be synthesized by the body and must be obtained from the diet.

Nonessential Fatty Acids

Fatty acids that the human body can synthesize.

Linoleic Acid

An omega-6 fatty acid essential for human health, with key dietary sources including safflower, sunflower, and corn oils.

α-Linolenic Acid

An omega-3 fatty acid essential for human health, with key dietary sources including linseed/flax, soybean, and canola oils.

Micelles

Small, water-soluble aggregates formed after lipid digestion that facilitate the absorption of lipids. Made up of 2 MAG, FFA, lysopl, free cholesterol, phytosterol, fat-soluble vitamins, and bile salts

Enterohepatic Circulation

The circulation of bile acids from the intestine to the liver and back, playing a role in lipid digestion and absorption.

Bile

A digestive fluid produced by the liver that emulsifies fats, aiding in lipid digestion.

Lipoproteins

Specialized transport particles that carry lipids through the bloodstream.

Adipose Tissue

Tissue composed primarily of triacylglycerols, serving as a major energy reserve in the body.

Desaturase Enzymes

Enzymes required to introduce double bonds in fatty acid chains, specifically Δ¹² and Δ¹⁵ desaturases.

Fatty Acids

Building blocks of lipids, which can be saturated or unsaturated based on their chemical structure.

Hormones

Compounds that act as signaling molecules in the body, many of which are derived from lipids.

Bile Acids

Compounds derived from cholesterol that aid in the digestion and absorption of fats.

Physiological Homeostasis

The state of steady internal conditions maintained by living organisms, including energy balance.

Biochemical Machinery

The complex systems and processes that govern cellular function and metabolism.

Hydrophobic Molecules

Molecules that do not mix well with water, presenting challenges in digestion and absorption.

Energy Balance

The state of equilibrium between energy intake and energy expenditure in the body.

Fatty Acid Binding Proteins (FABP)

Intracellular proteins that bind to long-chain fatty acids, monoacylglycerols, and lysophospholipids, facilitating their transport to the smooth endoplasmic reticulum.

NPC1L1

A protein responsible for transporting cholesterol and phytosterols from the intestinal lumen into the enterocyte.

ABCG5 and ABCG8

Proteins that form a transporter to actively pump phytosterols and excess cholesterol back out of the enterocyte into the lumen.

Re-esterification

The process of reassembling absorbed monoacylglycerols and fatty acids into triacylglycerols inside the smooth endoplasmic reticulum.

Chylomicrons

Large lipoprotein particles that package newly synthesized lipids for transport out of the enterocyte.

VLDL (Very-Low-Density Lipoprotein)

Lipoprotein that transports endogenous lipids from the liver to peripheral tissues.

LIVER

• 2ND LARGEST AND 2ND LEAST

DENSE

• MADE UP OF:

• TAG (~50 - 60%)

• PHOSPHOLIPID

• CHOLESTEROL

• PROTEIN

• INTEGRAL PROTEIN: APO B100

IDL (Intermediate-Density Lipoprotein)

A transitional lipoprotein formed from VLDL as it loses TAGs, carrying TAGs and cholesterol esters.

3rd largest and 3rd least dense

Made up of:Made up of:

• TAG (~30%)

• Phospholipid

• Cholesterol

• protein

• Integral protein: APO B100

LDL LD

LDL (Low-Density Lipoprotein)

The primary carrier of cholesterol to peripheral tissues.

2ND SMALLEST AND 2ND MOST DENSE

• PRIMARY CARRIER OF CHOLESTEROL AND

CHOLESTEROL ESTERS

• STEROID HORMONES

• DELIVERS CHOLESTEROL TO CELLS

• MADE UP OF:

• TAG

• PHOSPHOLIPID

• CHOLESTEROL (~40 - 50%)

• PROTEIN

• INTEGRAL PROTEIN: APO B100

• 70 - 80% REMOVAL

HMG COA REDUCTASE

• ACYL COA:CHOLESTERYL ACYL

TRANSFERASE (ACAT) FORMATION OF

CHOLESTEROL ESTERS

• TRANSCRIPTION OF RECEPTOR

GENE

HDL (High-Density Lipoprotein)

Lipoprotein that gathers excess cholesterol from peripheral tissues and transports it back to the liver.

SMALLEST AND MOST DENSE

• LIVER AND INTESTINE

• REMOVES FREE CHOLESTEROL FROM CELLS AND LIPOPROTEINS

• MADE UP OF:

• TAG

• PHOSPHOLIPID

• CHOLESTEROL

• PROTEIN (~ 50%)

• APOLIPOPROTEIN: APO A1

Exogenous Pathway

The metabolic pathway for dietary fats, where newly formed chylomicrons are secreted from the enterocyte into the lymphatic system.

ApoB-48

Structural protein found in chylomicrons that is essential for their secretion from enterocytes.

ApoB-100

Key apolipoprotein found in VLDL and LDL, important for lipid transport.

ApoC-II

Apolipoprotein involved in the metabolism of chylomicrons and VLDL.

ApoE

Apolipoprotein that plays a role in the metabolism of lipoproteins and is found in chylomicrons, VLDL, and IDL.

ApoA-I

Key apolipoprotein found in HDL, important for cholesterol transport.

Lipoprotein Lipase (LPL)

Enzyme that hydrolyzes triacylglycerols in chylomicrons and VLDL, releasing fatty acids.

Chylomicron

Lipid transport particle that enters the bloodstream via the thoracic duct.

Chylomicron remnant

Smaller particle formed from a chylomicron after lipid loss, cleared by the liver.

Endogenous Pathway

Pathway managing lipids synthesized by the liver.

VLDL

Very low-density lipoprotein that transports endogenous triacylglycerols and cholesterol.

Intermediate-Density Lipoprotein (IDL)

Smaller, denser particle formed from VLDL after lipid removal.

Low-Density Lipoprotein (LDL)

Primary vehicle for delivering cholesterol to peripheral tissues.

LDL receptors

Cell surface receptors that recognize and take up LDL particles.

Reverse Cholesterol Transport

Pathway that removes excess cholesterol from the body.

Nascent HDL

High-density lipoprotein particles synthesized by the liver and intestine.

LCAT

Lecithin-cholesterol acyltransferase, enzyme that esterifies free cholesterol in HDL.

Insulin

Hormone that promotes the synthesis of LPL in the fed state.

HMG-CoA reductase

Rate-limiting enzyme in the cholesterol synthesis pathway.

Fatty Acid Synthesis (Lipogenesis)

Metabolic pathway converting excess energy into triacylglycerols for storage.

BASIC PROCESS: SEQUENTIAL ASSEMBLY OF "STARTER"

ACETYL COA WITH UNITS OF MALONYL COA

• EXCESS CARB INTAKE FAT SYNTHESIS

• FED STATE

• ↑ BLOOD GLUCOSE & INSULIN

• ↑ ATP

• OCCURS IN THE CYTOSOL

• LIVER

• ADIPOCYTES

FATTY ACID SYNTHESIS

Glucose

Pyruvate

Acetyl CoA

Citrate

Isocitrate

α-ketoglutarate

Isocitrate dehydrogenase

OAA

18

20

Acetyl-CoA carboxylase

Enzyme that catalyzes the major rate-limiting step in fatty acid synthesis.

Citrate

Substance that allosterically activates acetyl-CoA carboxylase, indicating an energy-rich state.

TCA cycle

Cycle that, when saturated with substrate, signals an energy-rich state.

Energy homeostasis

Balance of energy intake and expenditure, allowing storage of surplus calories.

Glucose

Primary precursor for the acetyl-CoA used in lipogenesis.

Fatty Acid Synthase Complex

A large, multi-enzyme cytosolic complex that carries out fatty acid synthesis.

MULTIENZYME COMPLEX

• ACETYL COA ATTACHES TO THE CONDENSING ENZYME SITE

• MALONYL COA ATTACHES TO THE ACYL CARRIER PROTEIN (ACP) SITE.

• ACETYL COA CONDENSES WITH MALONYL COA; REDUCTION,

DEHYDRATION, REDUCTION, REPEAT

Acyl Carrier Protein (ACP)

A key component of the fatty acid synthase system that holds the growing fatty acid chain during synthesis.

Four-step sequence of fatty acid synthesis

The repeating cycle of condensation, reduction, dehydration, and a second reduction that adds two-carbon units from malonyl-CoA to the growing chain.

NADPH

The coenzyme that serves as the hydrogen donor in the two reduction steps of fatty acid synthesis.

Palmitate

The primary product released from the fatty acid synthase complex, a 16-carbon fatty acid (16:0).

Cholesterol Synthesis

A key anabolic pathway for cholesterol production, regulated by the enzyme HMG-CoA reductase.

Statins

A class of cholesterol-lowering drugs that target HMG-CoA reductase.

Lipid Catabolism

The metabolic processes that mobilize and break down stored lipids to generate energy.

Triacylglycerols

The primary form of stored lipids in adipose tissue that are broken down during lipid catabolism.

Lipolysis

The hydrolysis of triacylglycerols stored within adipocytes, resulting in one glycerol molecule and three free fatty acids.

CATABOLISM OF TRIACYLGLYCEROLS AND FATTY ACIDS:

• MITOCHONDRIAL TRANSFER OF ACYL COA

• -OXIDATION OF FATTY ACIDS

ENERGY YIELD IN FATTY ACID OXIDATION

• FASTED STATE

• TAG DEGRADATION FROM ADIPOCYTES  RELEASED INTO THE BLOOD

KEY ENZYMES

• ADIPOSE TRIACYLGLYCEROL LIPASE (ATGL)

• HORMONE-SENSITIVE LIPASE (HSL)

• MONOACYLGLYCEROL LIPASE (MGL)

Free Fatty Acids &

Glycerol

Hormone-sensitive lipase (HSL)

A key enzyme that initiates and progresses lipolysis.

Perilipin 1

A key enzyme that works with hormone-sensitive lipase in the process of lipolysis.

Epinephrine

A hormone that stimulates lipolysis during energy need.

Atrial Natriuretic Peptide (ANP)

A peptide that stimulates lipolysis by binding to cell surface receptors.

Four Phases of Fatty Acid Catabolism

The complete breakdown of a fatty acid for energy production, consisting of lipolysis, activation, mitochondrial transport, and beta-oxidation.

Activation of Fatty Acids

The process where acyl-CoA synthetase attaches a coenzyme A molecule to a fatty acid, forming fatty acyl-CoA, consuming the equivalent of two ATP molecules.

Carnitine Shuttle System

The system that transports fatty acyl-CoA from the cytosol into the mitochondrial matrix.

Carnitine Acyltransferase I (CAT I)

An enzyme involved in the carnitine shuttle system that facilitates the transport of fatty acyl-CoA.

Carnitine Acyltransferase II (CAT II)

An enzyme involved in the carnitine shuttle system that facilitates the transport of fatty acyl-CoA.

Beta-Oxidation

A cyclical process inside the mitochondrial matrix that systematically breaks down fatty acyl-CoA chains by removing two-carbon units.

Energy Yield from Beta-Oxidation

The process and products resulting from the four-step cycle that cleaves a two-carbon fragment from the fatty acyl-CoA chain.

Acetyl-CoA

One molecule produced from beta-oxidation.

NADH

One molecule produced from beta-oxidation.

FADH₂

One molecule produced from beta-oxidation.

Beta-Oxidation Cycles

The number of cycles required is given by the formula (n/2) - 1, where n is the number of carbons.

Total Products from 7 cycles

7 NADH and 7 FADH₂ are produced, and the 16-carbon chain is cleaved into 8 acetyl-CoA molecules.

Gross ATP Production

Calculated as 8 Acetyl-CoA x 10 ATP/cycle + 7 NADH x 2.5 ATP/NADH + 7 FADH₂ x 1.5 ATP/FADH₂ = 108 ATP.

Net ATP Yield

The net yield from the complete oxidation of palmitate is 106 ATP after subtracting 2 ATP equivalents used for initial activation.

Regulation of Beta-Oxidation

Primarily regulated by substrate availability; fasting hormones like glucagon stimulate lipolysis.

Ketogenesis

A metabolic pathway occurring predominantly in the liver during prolonged fasting or starvation.

Oxaloacetate

Depletion of this molecule triggers ketogenesis as acetyl-CoA accumulates.

Ketone Bodies

Primarily acetoacetate and β-hydroxybutyrate, formed from excess acetyl-CoA in ketogenesis.

HMG-CoA

The metabolic fate is determined by a critical enzymatic branch point between cholesterol synthesis and ketogenesis.

HMG-CoA Lyase

Enzyme that cleaves HMG-CoA to form acetoacetate in ketogenesis.

Substrates of FABP

Initially identified for carrying fatty acids, but also transport lysophospholipids and monoacylglycerols.

Sterol Carrier Proteins

Manage the transport of sterols within the enterocyte.

MAG/DAG Acyltransferase

Enzymes responsible for the re-esterification of lipids in the endoplasmic reticulum.

Re-esterification process

Converts the absorbed digestion products back into complex lipids suitable for transport.

Acyltransferases

Enzymes that catalyze the transfer of fatty acid-CoA molecules onto the backbone molecules.

Monoacylglycerol (MAG)

A molecule that is converted into triacylglycerol (TAG) by the transfer of fatty acid-CoA.

Triacylglycerol (TAG)

A complex lipid produced from monoacylglycerol (MAG) through the action of acyltransferases.

Lysophospholipid (LysoPL)

A molecule that is converted into phospholipid (PL) by the transfer of fatty acid-CoA.