chapter 11 lipids and amino acids

Dietary fats — primary component

Triacylglycerols (primary); also cholesterol, cholesteryl esters, phospholipids, and free fatty acids

Where does most lipid digestion occur?

Small intestine (duodenum)

Emulsification

Mixing of fat and water to form an emulsion; increases lipid surface area for greater enzymatic access; occurs in the duodenum; aided by bile

Bile — contents

Bile salts, pigments, and cholesterol

Bile — origin and storage

Secreted by the liver; stored in the gallbladder

Pancreatic enzymes for lipid digestion

Pancreatic lipase, colipase, and cholesterol esterase

Products of pancreatic lipid digestion

2-monoacylglycerol, free fatty acids, and cholesterol

Micelles

Clusters of amphipathic lipids soluble in the aqueous intestinal lumen; formed from free fatty acids, cholesterol, 2-monoacylglycerol, and bile salts; vital for lipid transport from duodenum to ileum

What happens at the end of the ileum?

Bile salts are actively reabsorbed and recycled; remaining fat passes to the colon

How are lipids absorbed into intestinal cells?

Micelles diffuse to the brush border; digested lipids are absorbed into the mucosa, re-esterified into triacylglycerols and cholesteryl esters, then packaged into chylomicrons

Chylomicrons — how they leave the intestine

Exit via lacteals (lymphatic vessels) and re-enter the bloodstream through the thoracic duct into the left subclavian vein

Short-chain fatty acid absorption

Absorbed directly across the intestine into the blood via simple diffusion

Long-chain fatty acid absorption

Absorbed as micelles; assembled into chylomicrons for release into the lymphatic system

Post-absorptive state

At night, the body uses energy stores (fatty acids released from adipose tissue) rather than food for fuel

Hormone-sensitive lipase (HSL)

Hydrolyzes triacylglycerols in adipose tissue → free fatty acids + glycerol; activated by epinephrine and cortisol (and fall in insulin); does NOT respond to glucagon; requires LPL for metabolism of chylomicrons and VLDL

Lipoprotein lipase (LPL)

Releases free fatty acids from triacylglycerols in chylomicrons and VLDL; necessary for their metabolism

How are free fatty acids transported in blood?

Bound to albumin, a carrier protein

Lipoproteins — overview

Aggregates of apolipoproteins and lipids; transport triacylglycerols and cholesterol in the blood; density increases as protein % increases

Lipoprotein density order (memory trick)

'Chubby Vultures Inevitably Love HDL' → Chylomicrons (least dense) → VLDL → IDL → LDL → HDL (most dense)

Chylomicrons

Least dense lipoprotein; transport DIETARY triacylglycerols, cholesterol, and cholesteryl esters from intestine to tissues; assembled in intestinal lining

VLDL

Very-low-density lipoprotein; produced in liver; transports NEWLY SYNTHESIZED triacylglycerols from liver to peripheral tissues; contains fatty acids from excess glucose or chylomicron remnants

IDL

Intermediate-density lipoprotein (VLDL remnant); transition between triacylglycerol and cholesterol transport; some reabsorbed by liver, some picks up cholesteryl esters from HDL → becomes LDL

LDL

Low-density lipoprotein; primarily transports cholesterol to tissues for biosynthesis and cell membrane maintenance — the 'bad' cholesterol carrier

HDL

High-density lipoprotein; synthesized in liver and intestines; primary function is reverse cholesterol transport — picks up excess cholesterol from blood vessels for excretion; also delivers cholesterol to steroidogenic tissues

Apolipoproteins (apoproteins)

Protein components of lipoproteins; act as receptor molecules and control interactions between lipoproteins

What do chylomicrons and VLDL primarily carry?

Triacylglycerols (also small amounts of cholesteryl esters)

What do LDL and HDL primarily carry?

Cholesterol

Roles of cholesterol

Cell membrane biosynthesis and stability/fluidity; precursor to bile acids/salts; precursor to steroid hormones (steroidogenesis); precursor to vitamin D

Sources of cholesterol

Dietary (via LDL or HDL) OR de novo synthesis in the liver from acetyl-CoA + ATP

Citrate shuttle (cholesterol synthesis)

Carries mitochondrial acetyl-CoA into the cytoplasm where cholesterol synthesis occurs; NADPH (from pentose phosphate pathway) supplies reducing equivalents

Rate-limiting step of cholesterol synthesis

Synthesis of mevalonic acid in the smooth ER; catalyzed by HMG-CoA reductase

Regulation of cholesterol synthesis

Inhibited by high cholesterol (feedback inhibition); stimulated by insulin; also depends on HMG-CoA reductase gene expression

CETP (cholesteryl ester transfer protein)

Catalyzes transition from IDL to LDL by transferring cholesteryl esters from HDL to IDL

LCAT (lecithin-cholesterol acyltransferase)

Enzyme in the bloodstream activated by HDL apoproteins; adds a fatty acid to cholesterol → soluble cholesteryl esters in HDL; these can be transferred to IDL → LDL

Fatty acid structure

Long-chain carboxylic acids; carbon 1 = carboxyl carbon; carbon 2 = alpha carbon; occur as salts capable of forming micelles or esterified to other compounds

Fatty acid nomenclature

Written as carbons:double bonds (e.g., 16:0 = palmitic acid); position and cis/trans isomerism of double bonds can also be specified

Omega (ω) numbering system

Describes the position of the last double bond relative to the END of the fatty acid chain; identifies the major precursor fatty acid

Essential fatty acids

Alpha-linolenic acid and linoleic acid; maintain cell membrane fluidity; must come from diet because humans cannot synthesize enough unsaturated fatty acids

Nontemplate synthesis

Synthesis that does not rely on nucleic acid coding; carbohydrate and lipid synthesis are primary examples

Where does fatty acid synthesis occur?

Primarily in the liver; products transported to adipose for storage; synthesis occurs in the CYTOPLASM from acetyl-CoA transported out of the mitochondria

5 steps of fatty acid synthesis (memory trick)

'A BRaDS' → Activation, Bond formation, Reduction, Dehydration, Second reduction; repeated 8 times to form palmitic acid (16:0)

How many acetyl-CoA units to make palmitate?

8 acetyl-CoA units (cycle repeated 8 times)

Acetyl-CoA shuttling mechanism

After a large meal, excess acetyl-CoA combines with OAA → citrate (in TCA); citrate diffuses to cytosol; citrate lyase splits it back into acetyl-CoA + OAA; OAA returns to mitochondria

Acetyl-CoA carboxylase

Rate-limiting enzyme of fatty acid synthesis; adds CO2 to acetyl-CoA → malonyl-CoA; requires biotin and ATP; activated by insulin and citrate

Fatty acid synthase (palmitate synthase)

Large multienzyme cytosolic complex; contains ACP (requires pantothenic acid/B5); requires NADPH; induced by high insulin after a carb-heavy meal

Major enzymes of fatty acid synthesis

Acetyl-CoA carboxylase (rate-limiting) and fatty acid synthase

Beta-oxidation — overview

Primary form of fatty acid catabolism; occurs in the mitochondria; stimulated by glucagon; inhibited by insulin; opposite of fatty acid synthesis

3 stages of beta-oxidation

1. Activation (fatty acid → acyl-CoA) 2. Entry into mitochondria (via carnitine shuttle) 3. Beta-oxidation in mitochondrial matrix

Fatty-acyl-CoA synthetase

Activates fatty acids by attaching CoA; product = fatty acyl-CoA (e.g., palmitoyl-CoA has 16-carbon acyl group)

Carnitine shuttle

Required for long-chain fatty acids (can't cross inner mitochondrial membrane alone); carnitine carries the acyl group across; short- and medium-chain fatty acids diffuse freely

Rate-limiting enzyme of beta-oxidation

Carnitine acyltransferase I

4 steps of beta-oxidation (memory trick)

'OHOC' → Oxidation (FAD→FADH2), Hydration (adds H2O), Oxidation (NAD+→NADH), Cleavage (releases acetyl-CoA + shorter acyl-CoA)

Products of each beta-oxidation cycle

1 acetyl-CoA + 1 FADH2 + 1 NADH + shortened acyl-CoA

Fate of acetyl-CoA in muscle/adipose

Enters citric acid cycle for energy

Fate of acetyl-CoA in liver

Stimulates gluconeogenesis by activating pyruvate carboxylase; in fasting, excess → ketone bodies (cannot be converted back to glucose)

Odd-chain fatty acid oxidation

Final cycle yields 1 acetyl-CoA + 1 propionyl-CoA (from 5-carbon fragment)

Propionyl-CoA carboxylase

Converts propionyl-CoA → methylmalonyl-CoA; requires biotin (B7)

Methylmalonyl-CoA mutase

Converts methylmalonyl-CoA → succinyl-CoA; requires cobalamin (B12); succinyl-CoA enters TCA or gluconeogenesis

Unsaturated fatty acid oxidation — extra enzymes

Enoyl-CoA isomerase (for monounsaturated — rearranges cis double bond at 3,4 to trans at 2,3) and 2,4-dienoyl-CoA reductase (for polyunsaturated — converts two conjugated double bonds to one)

Ketone bodies

Acetoacetate and 3-hydroxybutyrate; formed in the fasting state when excess acetyl-CoA accumulates in the liver; used for energy by peripheral tissues

Ketogenesis

Occurs in liver mitochondria during fasting; HMG-CoA synthase forms HMG-CoA from acetyl-CoA; HMG-CoA lyase breaks it down → acetoacetate → 3-hydroxybutyrate; acetone is a minor non-energy side product

Ketolysis

Regenerates acetyl-CoA from ketone bodies for energy in peripheral tissues; requires succinyl-CoA:acetoacetyl-CoA transferase (thiophorase) — found ONLY in tissues outside the liver

Why can't the liver use its own ketone bodies?

Thiophorase (enzyme needed for ketolysis) is absent in liver cells

Brain and ketone bodies

Can derive up to 2/3 of its energy from ketone bodies during prolonged starvation

Is protein digestion common for metabolism?

No — metabolism is directed toward conserving tissues, especially the heart and brain; protein catabolism only occurs under starvation conditions

Where does protein digestion begin?

Stomach — via pepsin

Pancreatic proteases

Trypsin, chymotrypsin, carboxypeptidases A and B; all secreted as inactive zymogens

Where is protein digestion completed?

Small intestine — brush-border enzymes dipeptidase and aminopeptidase; products = amino acids and di/tripeptides

Amino acid absorption

Luminal membrane: secondary active transport linked to sodium; basal membrane: simple and facilitated diffusion into bloodstream

Primary sites of protein catabolism

Muscle and liver

Transamination

Loss of an amino group from an amino acid; remaining carbon skeleton used for energy

Glucogenic amino acids

All amino acids EXCEPT leucine and lysine; can be converted to glucose via gluconeogenesis

Ketogenic amino acids (memory trick)

'LIFTTWY' → Leucine, Isoleucine, Phenylalanine, Threonine, Tryptophan, Tyrosine, (and Lysine); converted to acetyl-CoA or ketone bodies

Fate of amino groups after transamination/deamination

Converted to ammonia → potentially toxic → excreted via the urea cycle in the liver

Urea cycle

Occurs in the liver; primary way of removing excess nitrogen from the body

Fate of amino acid side chains

Basic side chains → feed into urea cycle; other side chains → act like carbon skeletons → energy via gluconeogenesis or ketone productio