lipid and protein metabolism

what are triacylglycerols (TAGs)?

• aka triglycerides, triacylglycerides

• 3 fatty acids esterified to a glycerol molecule: can be different lengths and saturation states

• highly concentrated store of energy: 9 kcal/g vs 4 kcal/g for glycogen

what are bile salts?

• help absorption of fat into the small intestine
• dietary large fat globules must be broken down into smaller particles called micelles before being absorbed by the intestines
• produced in the liver and stored in the gall bladder
• act as detergents and are used to solubilize triacylglycerols

what are pancreatic lipases?

hydrolyze the ester bonds of the triacylglycerols while in the micelles

what is the nomenclature of fatty acids?

• alpha end contains carboxylic acid group

• omega (ω) end contains methyl group

what is the chain length of fatty acids?

• short: <8 carbons
• medium: 8-12 carbons
• long: >12 carbons

what are the number and positions of double bonds of fatty acids?

• saturated (SFA): single C-C bonds
• unsaturated: double bonds
• monunsaturated (MUFA): one double bond
• polyunsaturated (PUFA): >2 double bonds

what are cis vs trans (unsaturated) fatty acids?

• cis: H atoms positioned on same side of double bond
• trans: H atoms are on opposite sides of double bond
• trans fatty acids in food

what is the structure of fatty acids?

• methyl/omega end: often written as -CH3
• fatty acid backbone
• carboxylic/alpha end: often written as -COOH

what are trans fatty acids?

• primary dietary source for trans fats in processed foods (e.g. fried foods, commercial baked goods, margarine)
• artificial trans fats are created in an industrial process that adds H to liquid vegetable oils to make them more solid
• may be a bigger risk factor for heart disease than saturated fatty acids
• increase LDL and decrease HDL
• dietary guidelines: keep intake as low as possible

what are dietary fatty acids?

• fatty acids with chain lengths of 4-10 C are found in significant quantities in milk
• structural lipids and triacylglycerols contain primarily fatty acids of at least 16 C
• essential fatty acids: linoleic acid
• precursor of prostaglandins: arachidonic acid

what are linolenic and linolenic acid?

• linoleic acid: pro-inflammatory

• linolenic: anti-inflammatory

• sources: salmon, mackerel, albacore, sardines, halibut

• mammals lack the enzymes to introduce double bonds beyond C-9 in FA: cannot synthesize linoleate and linolenate

what is the activation of fatty acids?

fatty acyl CoA synthetase (FACS) reactions occurs on the mitochondrial membrane

what is β-oxidation?

• repeated cycle of 4 reactions resulting in cleavage of C3-C2 (Cβ-C⍺) bond of fatty acyl-CoA

• products of each cycle are FADH2, NADH, and acetyl-CoA

• no ATP requirement

what is needed for fatty acid synthesis?

acetyl CoA, NADPH, and ATP are provided by glucose metabolism

what is needed for TAG synthesis?

glycolysis provides the glycerol backbone

what is fatty acid synthesis?

• end product: palmitate (16C)
• C units are added to a growing fatty acid chain 2 C per cycle (7 cycles yield 16C palmitate)
• ATP is required as an energy source to synthesize malonyl-CoA
• occurs in the cytoplasm, whereas fatty acid oxidation occurs in mitochondria

when can ketone bodies be used as an alternative fuel in FAS?

• low blood glucose
• prolonged fasting
• diabetes
• dietary carb restriction
• acetyl-CoA accumulation

what is the process of fatty acid β oxidation?

1. fatty acids are converted into FA-carnitine to enter the mitochondria

• regulated by Malonyl CoA: when its levels are low, the "gatekeeper" enzyme CPTI allows fat to enter for burning

2. the fatty acid (as FA-CoA) is chopped down step-by-step

• this process produces NADH and FADH₂, which the cell uses to generate ATP

• if ATP levels are already high, the cell slows this process down

3. the breakdown ends with Acetyl CoA, which has two main paths

• TCA Cycle: joins with oxaloacetate to produce energy via the citric acid cycle

• ketogenesis: if the TCA cycle is overwhelmed or oxaloacetate is being used for gluconeogenesis, the acetyl CoA is diverted to create ketone bodies, which serve as an alternative fuel for the brain and muscles

4. oxaloacetate is diverted toward gluconeogenesis (making new glucose)

• often happens simultaneously with fat burning to maintain blood sugar levels

what is ketone body synthesis?

• formed principally in liver
• occurs in mitochondria

what are the plasma concentrations of FAs and ketone bodies in different nutritional states?

normal, fasting, starvation (mmol/L):

• fatty acids: 0.6, 1.0, 1.5
• acetoacetate: <0.1, 0.2, 1-2
• β-hydroxybutyrate: <0.1, 1, 5-10

what are the types of diabetes?

type 1, insulin-dependent:

• often begins in childhood

• characterized by the pancreas's producing inadequate levels of insulin

• can result from pancreatic damage by viral infections or genetic mutations

type 2, insulin-resistant:

• characteristic of adults

• insulin is produced, but insulin receptors are not responsive

• a person will not respond to insulin therapy

gestational:

• can occur during pregnancy

• blood glucose levels usually return to normal after the baby is born

what happens in the absence of insulin?

• leads to diabetic ketoacidosis
• liver doesn't import glucose and cannot provide oxaloacetate to process acetyl-CoA
• no inhibition of mobilization of FAs from adipose tissue
• liver oxidizes FAs, acetyl-CoA accumulates
• liver produces large amount of ketone bodies, secreted into the blood
• blood pH drops, disturbs function in CNS
• acetone smell in breath: diabetes, alcohol use, ketogenic diet

what is ketoacidosis?

• ketosis occurs in cases in diabetes, diets high in fat, and starvation
• ketone bodies are acidic: when they accumulate, they lower blood pH below 7.4

what are the main categories of amino acid metabolism?

1. anabolism (building up)

• protein synthesis: building structural proteins, enzymes, and hormones

• nitrogenous compounds: creating specialized molecules like DNA bases, neurotransmitters, and antioxidants

2. catabolism (breaking down energy)

• amino acids are broken down through processes like deamination

• ⍺-ketoacids: C skeletons left over after removing N that can enter the TCA cycle, be turned into glucose, or stored as fat/ketone bodies

3. waste management (N disposal)

• urea cycle: converting ammonia into urea to be excreted by the kidneys

• glutamine synthesis: safe way to transport N through the blood

what are the amino acid requirements of humans?

nutritionally essential:

• arginine: nutritionally semiessential; synthesized at rates inadequate to support growth of children

• histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine n

nutritionally nonessential:

• glutamine: semiessential under pathological conditions

• alanine, asparagine, aspartate, cysteine, glutamate, glycine, proline, serine, tyrosine

what is glutamate?

• central player of transamination reactions
• synthesis catalyzed by glutamic pyruvic transaminase (GPT), aka alanine transaminase (ALT)

what is transamination?

amino acid + ⍺-ketoglutarate ←aminotransferase (transaminase)→ ⍺-keto acid + glutamate

what is the conversion of Gln to ⍺KG?

• used to fuel the TCA cycle

⍺KG ←glue dehydrogenase (GLUD)→ Glu ←glutaminase (GLS)- glutamine -Gln synthetase (GS)→ Gln

what is glutamine?

can be used as a C source for the TCA cycle through an anaplerotic reaction

what is the process of using glutamine as a C source for the TCA cycle?

1. glutamine is transported into the cell through the SLC1A5 transporter

2. inside the cell, glutaminase converts glutamine into glutamate

3. glutamate enters the mitochondria, where the enzyme GLUD (glutamate dehydrogenase) converts it to ⍺KG

4. ⍺KG then flows through the TCA cycle to produce other intermediates such as succinate, fumarate, malate, and OAA

how are C skeletons used for energy?

• glucogenic: TCA cycle intermediates or pyruvate (gluconeogenesis)
• ketogenic: acetyl CoA, acetoacetyl CoA, or acetoacetate

what is the breakdown of carbs, amino acids, and fatty acids?

• all can be broken down to acetyl-CoA
• all can generate energy through the TCA cycle