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Клиническая биохимия

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Part I ● Biochemistry

Stage	Carbohydrate		Protein	Fat
Stage

I	Glucose		Amino acids	Fatty acids

II		Pyruvate
		Pyruvate	Acetyl-CoA
			Acetyl-CoA

III				TCA
				Cycle	2 CO2
					2 CO2
		3 NADH & FADH2			O2
IV		e–		ETC	O2
IV		e–		ETC	H2O
			ATP synthase		H2O
			ATP synthase

		ADP + Pi ATP
	Figure I-11-1. Energy from Metabolic Fuels

METABOLIC ENERGY STORAGE

ATP is a form of circulating energy currency in cells. It is formed in catabolic pathways by phosphorylation of ADP and may provide energy for biosynthesis (anabolic pathways). There is a limited amount of ATP in circulation. Most of the excess energy from the diet is stored as fatty acids (a reduced polymer of acetyl CoA) and glycogen (a polymer of glucose). Although proteins can be mobilized for energy in a prolonged fast, they are normally more important for other functions (contractile elements in muscle, enzymes, intracellular matrix, etc.).

In addition to energy reserves, many other types of biochemicals are required to maintain an organism. Cholesterol is required for cell membrane structure, proteins for muscle contraction, and polysaccharides for the intracellular matrix, to name just a few examples. These substances may be produced from transformed dietary components.

REGULATION OF FUEL METABOLISM

The pathways that are operational in fuel metabolism depend on the nutritional status of the organism. Shifts between storage and mobilization of a particular fuel, as well as shifts among the types of fuel being used, are very pronounced in going from the well-fed state to an overnight fast, and finally to a prolonged state of starvation. The shifting metabolic patterns are regulated mainly by the insulin/glucagon ratio. Insulin is an anabolic hormone which promotes fuel

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storage. Its action is opposed by a number of hormones, including glucagon, epinephrine, cortisol, and growth hormone. The major function of glucagon is to respond rapidly to decreased blood glucose levels by promoting the synthesis and release of glucose into the circulation.

Anabolic and catabolic pathways are controlled at 3 important levels:

•Allosteric inhibitors and activators of rate-limiting enzymes

•Control of gene expression by insulin and glucagon

•Phosphorylation (glucagon) and dephosphorylation (insulin) of rate-limiting enzymes

Well-Fed (Absorptive) State

High-Yield

Immediately after a meal, the blood glucose level rises and stimulates the release of insulin. The 3 major target tissues for insulin are liver, muscle, and adipose tissue. Insulin promotes glycogen synthesis in liver and muscle. After the glycogen stores are filled, the liver converts excess glucose to fatty acids and triglycerides. Insulin promotes triglyceride synthesis in adipose tissue and protein synthesis in muscle, as well as glucose entry into both tissues. After a meal, most of the energy needs of the liver are met by the oxidation of excess amino acids.

Two tissues—brain and red blood cells—are insensitive to insulin (are insulinindependent). The brain and other nerves derive energy from oxidizing glucose to CO2 and water in both the well-fed and normal fasting states. Only in prolonged fasting does this situation change. Under all conditions, red blood cells use glucose anaerobically for all their energy needs.

Postabsorptive State

High-Yield

Glucagon and epinephrine levels rise during an overnight fast. These hormones exert their effects on skeletal muscle, adipose tissue, and liver. In liver, glycogen degradation and the release of glucose into the blood are stimulated. Hepatic gluconeogenesis is also stimulated by glucagon, but the response is slower than that of glycogenolysis. The release of amino acids from skeletal muscle and fatty acids from adipose tissue are both stimulated by the decrease in insulin and by an increase in epinephrine. The amino acids and fatty acids are taken up by the liver, where the amino acids provide the carbon skeletons and the oxidation of fatty acids provides the ATP necessary for gluconeogenesis.

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Part I ● Biochemistry

					RED		Pyruvate	Glucose	Glucose
					CELL			ATP
								ATP
				Bile			Lactate
				Bile salts	Cholesterol		Lactate	LIVER
				Bile salts	Cholesterol

				Fatty	Acetyl		Pyruvate	Glucose	Glucose
				acids	CoA		Pyruvate	Glucose	Glucose
				acids	CoA
			Glycerol-P			Urea
				Fat	CO2	Urea		GLYCOGEN	Glucose
					ATP	Amino acids			Glucose
				Glycerol VLDL		Amino acids		Blood	Pyruvate
FAT	Fatty			Glycerol VLDL		Amino acids		Blood	Acetyl
FAT	Fatty
	acids
				Chylo-			Amino		CoA
Glycerol-P	Acetyl			Chylo-	Acetyl CoA		Amino	PROTEIN	CO2
Glycerol-P	Acetyl			microns	Acetyl CoA		acids	PROTEIN	CO2
	CoA	CO2		Pyruvate		CO2			ATP
Pyruvate						CO2			ATP
						ATP			BRAIN
						ATP
		ATP			Glucose			GLYCOGEN
	Glucose			Glucose	Glucose			GLYCOGEN
ADIPOSE TISSUE							MUSCLE
ADIPOSE TISSUE
					Glucose
			Figure I-11-2. Metabolic Profile of the Well-Fed (Absorptive) State

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Chapter 11 ● Energy Metabolism

			RED	Pyruvate	Glucose
			CELL		ATP
					ATP
				Lactate	CORI CYCLE
		LIVER		Lactate	Glycerol-P
				Lactate	Glycerol-P
		Fatty	Acetyl	Pyruvate	Glucose	Glucose
		acids	CoA	Pyruvate	Glucose	Glucose
		acids	CoA
		Glycerol-P	CO2	Urea
		Glycerol-P	ATP	Urea		Glucose
			ATP	Alanine	GLYCOGEN	Glucose
			Ketone	Alanine	GLYCOGEN
	Glycerol		bodies			Pyruvate
	Glycerol					Pyruvate
	Fatty	Fatty acid	Ketone	Alanine	Blood	Acetyl
FAT	Fatty	Fatty acid	bodies	Alanine	Blood	Acetyl
FAT	acids	albumins				CoA
				Amino		CO2
	Acetyl		Ketone	Amino	PROTEIN	ATP
	Acetyl		Ketone	acids	PROTEIN
	CoA		bodies
	CO2		Fatty			BRAIN
	CO2		acids
	ATP		Acetyl	CO2
ADIPOSE TISSUE			CoA	ATP
				ATP	MUSCLE
					MUSCLE

Figure I-11-3. Metabolic Profile of the Postabsorptive State

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Part I ● Biochemistry

Note

Carbohydrate (4 kcal/gm)

Protein (4 kcal/gm)

Fat (9 kcal/gm)

Alcohol (7 kcal/gm)

Note

A recommended 2,100-kcal diet consisting of 58% carbohydrate, 12% protein, and 30% fat content:

305 g of carbohydrate

0.58 × 2,100 kcal = 1,218 kcal

1,218 kcal/4 kcal/g = 305 g

63 g of protein

0.12 × 2,100 = 252 kcal

252 kcal/4 kcal/g = 63 g

70 g of fat

0.30 × 2,100 = 630 kcal

630 kcal/9 kcal/g = 70 g

Prolonged Fast (Starvation)	High-Yield

MEDIUM YIELD

Levels of glucagon and epinephrine are markedly elevated during starvation. Lipolysis is rapid, resulting in excess acetyl-CoA that is used for ketone synthesis. Levels of both lipids and ketones are therefore increased in the blood. Muscle uses fatty acids as the major fuel, and the brain adapts to using ketones for some of its energy.

After several weeks of fasting, the brain derives approximately 2/3 of its energy from ketones and 1/3 from glucose. The shift from glucose to ketones as the major fuel diminishes the amount of protein that must be degraded to support gluconeogenesis. There is no “energy-storage form” for protein because each protein has a specific function in the cell. Therefore, the shift from using glucose to ketones during starvation spares protein, which is essential for these other functions. Red blood cells (and renal medullary cells) that have few, if any, mitochondria continue to be dependent on glucose for their energy.

PATTERNS OF FUEL METABOLISM IN TISSUES

Fats are much more energy-rich than carbohydrates, proteins, or ketones. Complete combustion of fat results in 9 kcal/g compared with 4 kcal/g derived from carbohydrate, protein, and ketones. The storage capacity and pathways for utilization of fuels varies by organ and nutritional status of the organism as a whole.

Table I-11-1. Preferred Fuels in the Well-Fed and Fasting States

Organ	Well-Fed	Fasting

Liver	Glucose and amino acids	Fatty acids

Resting skeletal muscle	Glucose	Fatty acids, ketones

Cardiac muscle	Fatty acids	Fatty acids, ketones

Adipose tissue	Glucose	Fatty acids

Brain	Glucose	Glucose (ketones in
		prolonged fast)

Red blood cells	Glucose	Glucose

Liver

Two major roles of the liver in fuel metabolism are to maintain a constant level of blood glucose under a wide range of conditions and to synthesize ketones when excess fatty acids are being oxidized.

•After a meal, the glucose concentration in the portal blood is elevated.

•The liver extracts excess glucose and uses it to replenish its glycogen stores. Any glucose remaining in the liver is then converted to acetyl CoA and used for fatty acid synthesis.

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Chapter 11 ● Energy Metabolism

•The increase in insulin after a meal stimulates both glycogen synthesis and fatty acid synthesis in liver. The fatty acids are converted to triglycerides and released into the blood as very low-density lipoproteins (VLDLs). In the well-fed state, the liver derives most of its energy from the oxidation of excess amino acids.

•Between meals and during prolonged fasts, the liver releases glucose into the blood. The increase in glucagon during fasting promotes both glycogen degradation and gluconeogenesis.

•Lactate, glycerol, and amino acids provide carbon skeletons for glucose synthesis.

Adipose Tissue

After a meal, the elevated insulin stimulates glucose uptake by adipose tissue. Insulin also stimulates fatty acid release from VLDL and chylomicron triglyceride (triglyceride is also known as triacylglycerol).

•Lipoprotein lipase, an enzyme found in the capillary bed of adipose tissue, is induced by insulin.

•The fatty acids that are released from lipoproteins are taken up by adipose tissue and re-esterified to triglyceride for storage.

•The glycerol phosphate required for triglyceride synthesis comes from glucose metabolized in the adipocyte.

•Insulin is also very effective in suppressing the release of fatty acids from adipose tissue.

•During the fasting state, the decrease in insulin and the increase in epinephrine activate hormone-sensitive lipase in fat cells, allowing fatty acids to be released into the circulation.

Recall Question

In a prolonged state of starvation, which of the following is the major source of energy for muscles?

A.Fatty acids

B.Glucose

C.Glycogen

D.Ketones

Answer: A

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Part I ● Biochemistry

Clinical Correlate

Because insulin is necessary for adipose cells to take up fatty acids from triglycerides, high triglyceride levels in the blood may be an indicator of untreated diabetes.

Skeletal Muscle

Resting muscle

The major fuels of skeletal muscle are glucose and fatty acids. Because of the enormous bulk, skeletal muscle is the body’s major consumer of fuel. After a meal, under the influence of insulin, skeletal muscle takes up glucose to replenish glycogen stores and amino acids that are used for protein synthesis. Both excess glucose and amino acids can also be oxidized for energy.

In the fasting state, resting muscle uses fatty acids derived from free fatty acids in the blood. Ketones may be used if the fasting state is prolonged. In exercise, skeletal muscle may convert some pyruvate to lactate, which is transported by blood to be converted to glucose in the liver.

Active muscle

The primary fuel used to support muscle contraction depends on the magnitude and duration of exercise as well as the major fibers involved. Skeletal muscle has stores of both glycogen and some triglycerides. Blood glucose and free fatty acids also may be used.

•Fast-twitch muscle fibers have a high capacity for anaerobic glycolysis but are quick to fatigue. They are involved primarily in short-term, high-intensity exercise.

•Slow-twitch muscle fibers in arm and leg muscles are well-vascularized and primarily oxidative. They are used during prolonged, low-to- moderate intensity exercise and resist fatigue. Slow-twitch fibers and the number of their mitochondria increase dramatically in trained endurance athletes.

•Short bursts of high-intensity exercise are supported by anaerobic glycolysis drawing on stored muscle glycogen.

•During moderately high, continuous exercise, oxidation of glucose and fatty acids are both important, but after 1–3 hours of sustained continuous exercise muscle glycogen stores become depleted and the intensity of exercise declines to a rate that can be supported by oxidation of fatty acids.

Cardiac Muscle

During fetal life, cardiac muscle primarily uses glucose as an energy source, but in the postnatal period there is a major switch to β-oxidation of fatty acids. Thus, in humans, fatty acids serve as the major fuel for cardiac myocytes. When ketones are present during prolonged fasting, they are also used. Thus, not surprisingly, cardiac myocytes most closely parallel the skeletal muscle during extended periods of exercise.

In patients with cardiac hypertrophy, this situation reverses to some extent. In the failing heart, glucose oxidation increases, and β-oxidation falls.

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Chapter 11 ● Energy Metabolism

Brain

Although the brain represents 2% of total body weight, it obtains 15% of the cardiac output, uses 20% of total O2, and consumes 25% of the total glucose. Therefore, glucose is the primary fuel for the brain.

•Blood glucose levels are tightly regulated to maintain the concentration levels that enable sufficient glucose uptake into the brain via GLUT 1 and GLUT 3 transporters.

•Because glycogen levels in the brain are minor, normal function depends upon continuous glucose supply from the bloodstream.

•In hypoglycemic conditions (<70 mg/dL), centers in the hypothalamus sense a fall in blood glucose level, and the release of glucagon and epinephrine is triggered.

•Fatty acids cannot cross the blood–brain barrier and are therefore not used at all.

•Between meals, the brain relies on blood glucose supplied by either hepatic glycogenolysis or gluconeogenesis. Only in prolonged fasts does the brain gain the capacity to use ketones for energy, and even then ketones supply only approximately 2/3 of the fuel; the remainder is glucose.

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Part I ● Biochemistry

Review Questions

Select the ONE best answer.

1.Two weeks after an episode of the flu, an 8-year-old boy with IDDM is brought to the emergency room in a coma. His breathing is rapid and deep, and his breath has a fruity odor. His blood glucose is 36.5 mM (normal: 4–6 mM [70–110 mg/dL]). The physician administers IV fluids, insulin, and potassium chloride. A rapid effect of insulin in this situation is to stimulate

A.gluconeogenesis in the liver

B.fatty acid release from adipose

C.glucose transport in muscle

D.ketone utilization in the brain

E.glycogenolysis in the liver

2.An alcoholic has been on a 2-week drinking binge during which time she has eaten little and has become severely hypoglycemic. Which additional condition may develop in response to chronic, severe hypoglycemia?

A.Glycogen accumulation in the liver with cirrhosis

B.Thiamine deficiency

C.Ketoacidosis

D.Folate deficiency

E.Hyperuricemia

3.After a routine physical exam and blood work, a woman with a normal weight for her height was advised that her lipid profile showed an elevation of blood triglycerides. The doctor advises the patient to lower fat consumption which disappoints her since she avidly consumes whole milk. The woman consults a nutritionist, who states that whole milk is 3.5% fat, which corresponds to approximately 11 g of fat in an 8 ounce serving. If she switches to drinking skim milk (nonfat), approximately how many additional grams of carbohydrates should she consume to make up for the loss of fat in the 8 ounce serving?

A.5 grams

B.11 grams

C.15 grams

D.25 grams

E.35 grams

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Chapter 11 ● Energy Metabolism

Answers

1.Answer: C. Insulin increases glucose transport in only two tissues, adipose and muscle. The major site of glucose uptake is muscle, which decreases hyperglycemia. Glucose and ketone transport and metabolism are insulin independent in the brain (choice D). Insulin would slow gluconeogenesis (choice A) and fatty acid release from adipose (choice B). Insulin would inhibit glycogenolysis in the liver (choice E).

2.Answer: C. Severe hypoglycemia lowers the insulin level and increases glucagon. This would favor fatty acid release from the adipose and ketogenesis in the liver.

3. Answer: D. You are expected to know that carbohydrates have 4 Kcal/gram, proteins have 4 Kcal/gram, fat has 9 Kcal/gram, and alcohol has 7 Kcal/gram. In this question, 11 grams of fat times 9 Kcal/gram = 99 Kcal which is rounded to 100 Kcal. Dividing 100 Kcal by 4 Kcal/gram of carbohydrate is 25 grams.

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