Chapter 4: Nutrient Metabolism

Liver

Receives

• blood from intestinal tract (monosacharides and AA)

• hormones from pancreas (insulin and glucagon)

Brain

• blood-brain barrier: prevents acces of lipid-soluble (hydrophobic) molecules to the brain, for example non-esterified FA

• relies on glucose or ketone bodies (in starvation)

Muscle tissue

= buffer store of phosphocreatine (= creatine phosphate)

• in equilibrium with ATP through action of creatine kinase

• Both contain protein

oxidative/ red fibres	white fibres
high content of mitochrondria high content of pigment myoglobin low intensity exercise oxidative metabolism store fat	low content of mitochrondria low content of pigment myoglobin high intensity exercise Anaerobic glycolysis store glycogen

Fat tissue

	White adipose tissue	Brown adipose tissue
mitrochondrial density	Low	High
Lipid droplets	Single, large	Multiple, small
Primary function	Energy storage (triglycerides → FA)	Thermogenesis (= heat production) by uncoupling fat oxidation from ATP production

kidneys

• renal arteries: supply blood to kidneys

• renal veins: return blood from kidneys

	cortex	medulla
blood supply	high	low
metabolism	aerobic metabolism (oxidation of glucose, FA and ketone bodies)	anaerobic metabolism of glucose

Regulation of energy metabolism (plasma glucose level maintenance)

1) Pancreas: islands of Langerhans

function: Maintenance plasma glucose at constant level

	insulin	glucagon
location of production	beta-cells	alpha-cells
stimulans	glucose ↑ AA ↑	glucose↓ AA ↑ ketone bodies ↑ FA ↑
Surpressor	/	rise in plasma glucose concentration
Reaction	stimulates target organs to store and conserve energy reserves decrease their rate of fuel oxidation	stimulates target organs to mobilize and liberate energy stores (e.g. lipids) increase their rate of fuel oxidation

2) Adrenal medulla

• function: secretes catecholamines

  • Adrenaline / epinephrine

  • Noradrenaline/ norepinephrine

• Increase activity of

  • Glycogen phosphorylase: glycogen → glucose (+: glucagon, -: insulin)

  • Hormone sensitive lipase: lipase in adipocytes which liberates FA from TAG (+: glucagon, -: insulin)

Carbohydrate metabolism

Steps before

1) Digestion of dietary carbohydrates (starch, sucrose, lactose) —> glucose, fructose, galactose

2) Absorbed and transported to the liver by the hepatic portal vein

3)

• part of fructose → glucose (intestinal epithelial cells)

• galactose + remaining fructose → glucose (liver)

Characteristics

• blood glucose concentration = dynamic equilibrium = around 5 mmol/L

  • dysfunction below 3 or above 11 mmol/L

• No G6P in muscle

• Glucose synthesis from fat not possible

• Limited fat synthesis from glucose

• Limited loss of glucose in the urine

Regulation blood glucose levels

Exceptions

• no glucose production from FA!!

• Ketone bodies = can be used as alternative energy source

	ketosis	ketoacidosis
what	Low level of ketones in the blood	Extremely high level of ketones in the blood
where	mitochondria of liver
cause	fasting, exercise, consumption of high-fat diet	(diabetics)
respons	supply of glucose stored as glycogen is depleted central nervous system must rely on glucose formed from glycerol and AA via gluconeogenesis	drop in pH of blood → impair the ability of the heart to contract → loss of consciousness

Carbohydrate metabolism: post-absorptive state vs carbohydrate rich breakfast

post-absorptive state

= last meal has been absorbed from the intestinal tract (e.g. overnight fast)

• insulin/glucagon ratio is reduced

• glucose enters the blood exclusively from the liver

  • glycogen → glucose

  • gluconeogenesis: lactate → glucose

  • muscle: AA (alanine)→ glucose

  • adipose tissue: glycerol → glucose

Carbohydrate rich breakfast

• glucose concentration ↑

• insulin secretion ↑ → insuling/glucagon ratio rises

• glucose to tissues

  • glycogen storage in liver and muscles

  • anaerobic glucose metabolism: lactate concentration ↑ → glycogen(liver)

Carbohydrate metabolism: Glycemic vs non-glycemic carbohydrates

Glycemic carbohydrates

Glycemic index (GI)

• = measure for the increase in blood glucose after consumption of standard amount of carbohydrate

• surface under blood-glucose response curve

• calculated relative to standard (glucose/ white bread)

High GI

• “fast” carbohydrates that quickly release glucose in the blood

Low GI

• '“slow” carbohydrates that release glucose more slowly into the bloodstream

Dependency GI

• food characteristics

• person-related factors

Non-glycemic carbohydrates

• do not directly influence the insulin response (eg. dietary fibre which is not digestible in the small intestine)

Fat metabolism

1) NEFA’s (Non-esterified fatty acids) are carried in the plasma bound to albumin

• each molecule albumin has binding sites for about three FAs

2) LP (lipoproteins) transport TAG and cholesterol

• core of TAG and cholesterol ester + outer layer of phospholipid and free cholesterol

• apolipoprotein = carrier protein

Fat metabolism: different types of LP’s

Type of Lipoproteins	From	To	Transport of …	Name
VLDL	Liver	Tissues	Triglycerides > cholesterol	/
LDL	Liver	Tissues	Cholesterol > triglycerides	“bad cholesterol” -> oxidized forms accumulate in the endothelial llining of blood vessels and form a risk for CVD
HDL	Tissues	Liver	Cholesterol > triglycerides	“good cholesterol”
Chylomicron	Intestine	Liver	Triglycerides > cholesterol	/

proteins:

• dietary TAG + cholesterol

Fat metabolism: maturation of CM and VLDL

1) Apo E or C-II transferred from HDL to CM or VLDL

2)

• Apo C-II = cofactor of lipoprotein lipase → catalyses hydrolysis of TAG in CM and VLDL to FFA’s → pass through capillary wall and enter tissue

  • prevents uptake of CM and VLDL by liver by covering apo-E and apo-B

  • with continued residence apo C-II is eventually transferred to HDL, which exposes both apo-E and apo-B

• Apo E and Apo B mediate the uptake of CM and VLDL remnants by the liver

Fat metabolism: NEFA’s after overnight fast and meal

• NEFA’s enter plasma from adipose tissue

• hormone sensitive lipase: regulates fat mobilization and opposing process

• Rate of utilization of NEFAs depend on the plasma concentration of the NEFAs (higher c → higher rate of utilization

• plasma NEFA concentration = inverse reflection of plasma glucose and insulin concentration

  • after overnight fast: insulin and glucose ↓ + NEFA ↑

  • after meal: shift from fat metabolism to carbohydrate metabolism

Fat metabolism: post-absorptive state vs after a carbohydrate-fat meal

Post-absorptive state

• hormone sensitive lipase (HSL) is activated by low insulin concentrations + adrenaline in plasma + noradrenaline in adipose tissue

• rate of NEFA release = regulated by FA re-esterification within the tissue

• NEFAs are liberated from adipose tissue and consumed by different tissues (eg. muscles, liver and renal cortex)

• in states of low insulin/glucagon ratio → production of ketone bodies in liver is stimulated

After carbohydrate-fat meal

• HSL will be suppressed by rising glucose and insulin concentrations

• increase adipose tissue glucose uptake

• production of G3P and re-esterification of FA within the tissue → increase glycolysis

• release of NEFAs from adipose tissue will be suppressed

• tissues receive no further supply of NEFAs and switch to glucose utilisation

• increased insulin/glucagon ratio → reduces rate of ketone body formation + release in the liver

Significant amount of fat also in meal!!

• TAG is absorbed and processed into CM → released in the blood (slower than glucose or AA, so peak is later) → CM escape the liver → insulin stimulates activity of lipoprotein lipase → TAG are removed from CM by adipose tissue, skeletal muscle and heart

Fat metabolism: Essential fatty acids

• animals do not have enzymes to introduce an unsaturated double bond between C-9 and therminal methyl group

• a good balance between omega-6 and omega-3

  • the same saturases and elongases are used

Linoleic acid C18:2\omega6	Linolenic acid C18:3\omega3
desaturase (double bond formation) + elongase (add 2 carbons)	desaturase (double bond formation) + elongase (add 2 carbons)
AA = Arachidonic acid C20:4\omega6	EPA = eicosa-pentanoic acid C20:5\omega3
→ PG = prostaglandines = mediate inflammation and pain → LT = leukotrienes = regulate function of white blood cells + stimulate contraction of smooth muscles	→ PG → LT → DHA = docosa hexanoic acid C22:6\omega3

Amino acid and protein metabolism

• AA can be oxidized

• Functions

  • Energy store

  • No fluctuation in e.g. glycogen store

• Important locations

  • skeletal muscle

  • liver

    • first organ through which AA pass after absorption

    • links AA - carbohydrate metabolism

    • Synthesis of urea

Amino acid and protein metabolism: Measuring turnover of essential amino acids

• Turnover = constant cycle of breakdown and replenishmen

1) incorporation of labelled AA (e.g. 13C-leucine)

2) total loss of labeled AA from extracellular pool during steady state = rate of infusion = specific activity x rate of synthesis

Scheme pg 4-16 !!

Amino acid and protein metabolism: transamination (enzyme, what, when to use, examples)

Enzyme

• transaminase

What

• transfer of an amino group from one AA to a 2-oxo acid

When to use

• link between AA and other aspects of metabolism

• route for oxidation of AA

Examples

• alanine - pyruvate

• Aspartate and oxaloacetate

• Glutamate and 2 oxoglutarate

Amino acid and protein metabolism: Essential amino acids - approaches

1) Nutritional approach: no synthesis possible at a rate required for normal growth and starting from normally available precursors

Example: Arg when Pro and Gln in the food is low

2) Metabolic apporach: an AA in which a structural unit can not be synthesized via de novo synthesis with human enzymes

Example: Thr

3) Functional approach: an AA that plays a role in maintenance of physiological functions within the body

Example: Phe as precursor for Adrenaline which is responsible for transmitter synthesis

Amino acid and protein metabolism: Non-essential /indispensable AA

can be synthesized de novo via transamination starting from a nitrogen source (ammonia) and a carbon source (alfa-keto acids)

Example: Glu

Amino acid and protein metabolism: Conditionally non-essential /indispensable AA

• are synthesized via a more complex pathway

• rate of synthesis is limited

Example: cys

Amino acid and protein metabolism: after a meal - AA interconversion in muscle

1) AA appear in portal vein

2) glutamine ↓ + alanine ↑

3) branched-chains AA leaving the liver (Val, Leu an Ileu) → skeletal muscle

4) Branched-chain AA can be transaminated and oxidized in the muscle → providing a source of energy for the muscle

• amino group transferred to 2-oxo-acid

  • → pyruvate → alanine

  • → 2-oxoglutarate → glutamate

• amino groups may form ammonia (at physiological pH) by glutamate dehydrogenase → ammonia + glutamate → (glutamine synthase) → glutamine

Conclusion: catabolism of branched chain AA leads to release of glutamine and alanine

5) Alanine is taken up by the liver for conversion to pyruvate to glucose

6) Glutamine is removed by the kidneys = important metabolic fuel

1. Alanine aminotransferate

2. Leucine, valine or other aminotransferase

3. Glutamine synthase

4. Glutamate dehydrogenase

5. Branched-chain 2-oxo-acid dehydrogenase

6. Muscle protein synthesis

7. Muscle protein breakdown (= proteolysis)