Lipid Metabolism

Chapter 7 Lipid Metabolism



I. Fatty Acid and Triacylglycerol Synthesis
A. Overview
1. Fatty acid and triacylglycerol synthesis occurs in the cytoplasm (oxidation occurs in the mitochondria) but its precursor, acetyl CoA, is formed in the mitochondrial matrix.

2. Fatty acid synthesis begins in the mitochondria with the formation of citrate as a 2-carbon transporter (acetyl CoA shuttle to cytoplasm).

3. Acetyl CoA carboxylase provides malonyl CoA to be used by the multienzyme complex, fatty acid synthase.

4. Regulation of fatty acid synthesis occurs at acetyl CoA carboxylase and is controlled by insulin, glucagon, and epinephrine.

5. Many phospholipids are derived from desaturated fatty acids, most of which are synthesized by the body.

B. Fatty acid and triacylglycerol synthesis: pathway reaction steps (Fig. 7-1)
1. Step 1
a. The citrate shuttle transports acetyl CoA generated in the mitochondrion to the cytosol (see Fig. 7-1).

b. Acetyl CoA cannot move across the mitochondrial membrane and must be converted into citrate.
image

7-1 Overview of fatty acid synthesis. Fatty acid synthesis primarily occurs in the fed state and is enhanced by insulin. Palmitate, a 16-carbon saturated fat, is the end product of fatty acid synthesis. NADPH is required for synthesis of palmitate and elongation of the chain.



Acetyl CoA: converted into citrate to cross the mitochondrial membrane


c. Acetyl CoA and oxaloacetate (OAA) undergo an irreversible condensation by citrate synthase to form citrate, which is transported across the mitochondrial membrane into the cytosol.

Excess dietary carbohydrate is the major carbon source for fatty acid synthesis, which occurs primarily in the liver during the fed state.


d. Citrate remaining in the mitochondrion is used in the citric acid cycle.

2. Step 2
a. Citrate is converted back to acetyl CoA and OAA by citrate lyase, an insulin-enhanced enzyme, in a reaction that requires ATP.

Fatty acid synthesis: acetyl CoA carboxylase is rate-limiting enzyme; occurs in cytosol in fed state


3. Step 3
a. Acetyl CoA is converted to malonyl CoA (see Step 5 below for disposal of OAA), an important intermediate in fatty acid synthesis, by acetyl CoA carboxylase in an irreversible rate-limiting reaction that consumes ATP and requires biotin as a cofactor.

b. Malonyl CoA inhibits carnitine acyltransferase I (see fatty acid oxidation below), preventing movement of newly synthesized fatty acids across the inner mitochondrial membrane into the matrix, where fatty acids undergo β-oxidation (futile cycling is thereby avoided).

Malonyl CoA: inhibits carnitine acyltransferase I


4. Step 4
a. Fatty acid synthase, a large multifunctional enzyme complex, initiates and elongates the fatty acid chain in a cyclical reaction sequence.

NADPH: produced by malic enzyme and by pentose phosphate pathway


b. Palmitate, a 16-carbon saturated fatty acid, is the final product of fatty acid synthesis.

c. One glucose produces 2 acetyl CoA, and each acetyl CoA contains 2 carbons; therefore, 4 glucose molecules are required to produce the 16 carbons of palmitic acid.

5. Step 5
a. OAA from citrate cleavage is converted to malate.

6. Step 6
a. Malate is converted to pyruvate by malic enzyme, producing 1 NADPH.

b. NADPH is required for synthesis of palmitate and elongation of fatty acids.

c. NADPH is produced in the cytosol by malic enzyme and the pentose phosphate pathway, which is the primary source.

7. Conversion of fatty acids to triacylglycerols in liver and adipose tissue (Fig. 7-2)
a. Step 1
(1) In the fed state, fatty acids synthesized in the liver or released from chylomicrons and VLDL by capillary lipoprotein lipase, are used to synthesize triacylglycerol in liver and adipose tissue (see Fig. 7-2).
image

7-2 Triacylglycerol (TG) synthesis in liver and adipose tissue. Sources of fatty acids range from synthesis in the liver to hydrolysis of diet-derived chylomicrons and liver-derived very-low-density lipoprotein (VLDL) (step 1). In the liver, glycerol 3-phosphate is derived from glycolysis or conversion of glycerol to glycerol 3-phosphate by liver glycerol kinase (step 2). In adipose tissue, glycerol 3-phosphate is derived only from glycolysis (step 6). DHAP, dihydroxyacetone phosphate.



Only liver can capture glycerol; glycerol kinase only found in liver


b. Step 2
(1) Glycerol 3-phosphate is derived from DHAP during glycolysis or from the conversion of glycerol into glycerol 3-phosphate by liver glycerol kinase.

(2) Glycerol 3-phosphate is the carbohydrate intermediate that is used to synthesize triacylglycerol.

Decrease triacylglycerol by decreasing carbohydrate intake.


(3) Decreasing the intake of carbohydrates is the most effective way of decreasing the serum concentration of triacylglycerol.

Glycerol kinase: present only in liver, converts glycerol to glycerol 3-phosphate (precursor for triacylglycerol synthesis)


c. Step 3
(1) Newly synthesized fatty acids or those derived from hydrolysis of chylomicrons and VLDL are converted into fatty acyl CoAs by fatty acyl CoA synthetase.

d. Step 4
(1) Addition of 3 fatty acyl CoAs to glycerol 3-phosphate produces triacylglycerol (TG) in the liver.

e. Step 5
(1) Liver triacylglycerols are packaged into VLDL, which is stored in the liver and transports newly synthesized lipids through the bloodstream to peripheral tissues.

f. Step 6
(1) Synthesis and storage of triacylglycerol in adipose tissue require insulin-mediated uptake of glucose, leading to glycolysis and production of glycerol 3-phosphate, which is converted to triacylglycerol by the addition of 3 fatty acyl CoAs.

(2) Insulin inhibits hormone-sensitive lipase, which allows adipose cells to accumulate triacylglycerol for storage during the fed state.

(3) Epinephrine and growth hormone activate hormone-sensitive lipase during the fasting state.

Hormone-sensitive lipase: inhibited by insulin, prevents lipolysis


C. Fatty acid and triacylglycerol synthesis: regulated steps (see Fig. 7-1, step 3)
1. Formation of malonyl CoA from acetyl CoA, the irreversible regulated step in fatty acid synthesis, is controlled by two mechanisms.
a. Allosteric regulation of acetyl CoA carboxylase
(1) Stimulation by citrate ensures that fatty acid synthesis proceeds in the fed state.

(2) End-product inhibition by palmitate downregulates synthesis when there is an excess of free fatty acids.

b. Cycling between active and inactive forms of acetyl CoA carboxylase
(1) High AMP level (low energy charge) inhibits fatty acid synthesis by phosphorylation of acetyl CoA carboxylase, which inactivates the enzyme.

(2) Glucagon and epinephrine (fasting state) inhibit acetyl CoA carboxylase by phosphorylation (by protein kinase); insulin (fed state) activates the enzyme by dephosphorylation (by phosphatase).

2. Inhibition of acetyl CoA carboxylase enhances the oxidation of fatty acids, because malonyl CoA is no longer present to inhibit carnitine acyltransferase I.

D. Fatty acid and triacylglycerol synthesis: unique characteristics
1. Synthesis of longer-chain fatty acids and unsaturated fatty acids
a. Chain-lengthening systems in the endoplasmic reticulum and mitochondria convert palmitate (16 carbons) to stearate (18 carbons) and other longer saturated fatty acids.

Palmitate is elongated in the endoplasmic reticulum and the mitochondrion; different elongation enzymes


2. Compartmentation prevents competition between fat synthesis and fat oxidation.
a. Synthesis in the cytosol ensures availability of NADPH from the pentose phosphate pathway.

b. The product, palmitate, cannot undergo immediate oxidation without transport back into the matrix.

Cytoplasmic synthesis of palmitate prevents its immediate oxidation


3. Adipose tissue does not contain glycerol kinase so the glycerol backbone of triacylglycerols must come from glycolysis.

E. Fatty acid synthesis: interface with other pathways
1. Desaturation of fatty acids to produce unsaturated fatty acids occurs in the endoplasmic reticulum in a complex process that requires oxygen either NADH or NADPH.

Saturated fatty acids lack double bonds.


Unsaturated fatty acids contain one or more double bonds.


2. Unsaturated fatty acids are stored in triglycerides, at the carbon 2 position.

3. Unsaturated fatty acids are used in making phosphoglycerides for cell membranes.

F. Fatty acid and triacylglycerol synthesis: clinical relevance
1. Fatty acid desaturase introduces double bonds at the carbon 9 position.

Fatty acid desaturase cannot create linolenic and linoleic acid, the essential fatty acids


a. The desaturase cannot create double bonds beyond carbon 9 preventing synthesis of linoleic and linolenic acid, the essential dietary fatty acids.

b. Deficiency of essential fatty acids produces dermatitis and poor wound healing.

Essential fatty acid deficiency: dermatitis and poor wound healing


2. An excess of fatty acids in the liver over the capacity for oxidation (e.g.. chronic alcoholics) results in resynthesis of triacylglycerol and storage in fat droplets, which produces a fatty liver.

II. Triacylglycerol Mobilization and Fatty Acid Oxidation (Fig. 7-3)
A. Overview
1. Fatty acids are mobilized in the fasting state by activating hormone-sensitive lipase.

2. Long-chain fatty acids are shuttled into the mitochondrial matrix by formation of acyl-carnitine esters; catalyzed by carnitine acyltransferase.

3. β-Oxidation of fatty acids consists of a repeating sequence of four enzymes to produce acetyl CoA.

4. Fatty oxidation in the liver is unregulated; the only point of regulation of fat oxidation is hormone-sensitive lipase in the fat cell.

5. Odd-chain fatty acids undergo normal β-oxidation until propionyl CoA is produced; propionyl CoA is converted by normal β-oxidation to methylmalonyl CoA and then to succinyl CoA.

6. Unsaturated fatty acids enter the normal β-oxidation pathway at the trans-enoyl step.

7. Deficiencies in fatty acid oxidation often produce nonketotic hypoglycemia.

B. Triacylglycerol mobilization and fatty acid oxidation: pathway reaction steps
image

7-3 Overview of lipolysis and oxidation of long-chain fatty acids. Lipolysis occurs in the fasting state. Carnitine acyltransferase I is the rate-limiting reaction and is inhibited by malonyl CoA during the fed state. Oxidation of fatty acids yields the greatest amount of energy of all nutrients. ETC, electron transport chain; TG, triacylglycerol.



Lipolysis occurs in the fasting state when fat is required for energy.


1. Step 1
a. Mobilization of stored fatty acids from adipose tissue (lipolysis)

b. Hormone-sensitive lipases in adipose tissue hydrolyze free fatty acids and glycerol from triacylglycerols stored in adipose tissue (see Fig. 7-3).

Hormone-sensitive lipase: activated by epinephrine and growth hormone, promotes lipolysis


c. Glycerol released during lipolysis is transported to the liver, phosphorylated into glycerol 3-phosphate by glycerol kinase, and used as a substrate for gluconeogenesis.

2. Step 2
a. Free fatty acids released from adipose tissue are carried in the bloodstream bound to serum albumin.

3. Step 3
a. The fatty acids are delivered to all tissues (e.g., liver, skeletal muscle, heart, kidney), except for brain and red blood cells.

b. The fatty acids dissociate from the albumin and are transported into cells, where they are acetylated by fatty acyl CoA synthetase in the cytosol, forming fatty acyl CoAs.

β-Oxidation of fatty acids: occurs in mitochondrial matrix in fasting state


4. Step 4
a. The carnitine shuttle transports long-chain (≥14-carbon) acetylated fatty acids across the inner mitochondrial membrane (see Fig. 7-3).

Fatty acids with 12 carbons or less enter the mitochondrion directly and are activated by mitochondrial synthetases.


b. Carnitine acyltransferase I (rate-limiting reaction) on the outer surface of the inner mitochondrial membrane removes the fatty acyl group from fatty acyl CoA and transfers it to carnitine to form fatty acyl carnitine.

c. Carnitine acyltransferase II on the inner surface of the inner mitochondrial membrane restores fatty acyl CoA as fast as it is consumed.

Medium-chain fatty acids are consumed directly by the mitochondria; they spare glucose for the brain and red cells and serve as a fuel for all other tissues


d. Medium-chain fatty acids are consumed directly by the mitochondria because they do not depend on the carnitine shuttle.
(1) Medium-chain triglycerides are an effective dietary treatment for an infant with carnitine deficiency.

(2) Medium-chain triglycerides spare glucose for the brain and red cells and serve as a fuel for all other tissues.

Carnitine acyltransferase I: rate-limiting enzyme of fatty acid oxidation; shuttle for fatty acyl CoA


5. Step 5
a. The oxidation system consists of four enzymes that act sequentially to yield a fatty acyl CoA that is two carbons shorter than the original and acetyl CoA, NADH, and FADH2.

b. Repetition of these four reactions eventually degrades even-numbered carbon chains entirely to acetyl CoA.

c. Acetyl CoA enters the citric acid cycle, which is also in the matrix.

Acetyl CoA: end product of even-chain saturated fatty acids


Total energy yield from oxidation of long-chain fatty acids (e.g., palmitate, stearate) is more than 100 ATP per molecule.


C. Triacylglycerol mobilization and fatty acid oxidation: regulated steps
1. Hormone-sensitive lipase is the only point in fat oxidation that is regulated by hormones.
a. Epinephrine and norepinephrine (i.e., fasting, physical exercise states) activate lipolysis by converting hormone-sensitive lipase to an active phosphorylated form by their activation of protein kinase.
(1) Perilipin coats the lipid droplets in adipose cells in the unstimulated state.

(2) Phosphorylation of perilipin removes it from the lipid droplet so that the activated hormone-sensitive lipase can act to mobilize free fatty acids.

Hormone-sensitive lipase is the only point in fat oxidation that is regulated by hormones.


b. Insulin (fed state) activates protein phosphatase, which inhibits lipolysis by converting hormone-sensitive lipase into an inactive dephosphorylated form.

c. Glucocorticoids, growth hormone, and thyroid hormone induce the synthesis of hormone-sensitive lipase, which provides more enzyme available for activation (i.e., activation by these hormones is indirect).

2. Carnitine acyltransferase I is inhibited allosterically by malonyl CoA to prevent the unintended oxidation of newly synthesized palmitate.
a. Malonyl CoA is the precursor used in fat synthesis, and its concentration reflects the active synthesis of palmitate.

b. Malonyl CoA is absent in the fasting state when fatty acids are being actively oxidized.

3. Reciprocal regulation of fatty acid oxidation and synthesis is illustrated in Table 7-1.

TABLE 7-1 Comparison of Fatty Acid Synthesis and Oxidation







































Property Synthesis Oxidation
Primary tissues Liver Muscle, liver
Subcellular site Cytosol Mitochondrial matrix
Carriers of acetyl and acyl groups Citrate (mitochondria → cytosol) Carnitine (cytosol → mitochondria)
Redox coenzyme NADPH NAD+, FAD
Insulin effect Stimulates Inhibits
Epinephrine and growth hormone effect Inhibits Stimulates
Allosterically regulated enzyme Acetyl CoA carboxylase (citrate stimulates; excess fatty acids inhibit) Carnitine acyltransferase I (malonyl CoA inhibits)
Product of pathway Palmitate Acetyl CoA


Fatty acids are the major energy source (9 kcal/g) in human metabolism.


High insulin-to-glucagon ratio (fed state) leads to fatty acid synthesis; low insulin-to-glucagon ratio (fasting state) leads to fatty acid degradation.


D. Triacylglycerol mobilization and fatty acid oxidation: unique characteristics
1. Ketone body synthesis (Fig. 7-4) serves as an overflow pathway during excessive fatty acid supply (usually from accelerated mobilization)

2. Ketone body synthesis occurs in the mitochondrial matrix during the fasting state when excessive β-oxidation of fatty acids results in excess amounts of acetyl CoA.
image

7-4 Ketone body synthesis. Synthesis of ketone bodies occurs primarily in the liver from leftover acetyl CoA. Ketone bodies are acetone, acetoacetate, and β-hydroxybutyrate, and they are used as fuel by muscle (fasting), brain (starvation), and kidneys.



Ketone bodies (acetone, acetoacetic acid, β-hydroxybutyric acid): fuel for muscle (fasting), brain (starvation), kidneys


a. Ketone bodies (acetone, acetoacetate, and β-hydroxybutyrate) are used for fuel by muscle (skeletal and cardiac), the brain (starvation), and the kidneys.

b. Ketone bodies spare blood glucose for use by the brain and red blood cells.

The liver is the primary site for ketone body synthesis; HMG CoA synthase is the rate-limiting enzyme.


3. The sequence of biochemical reactions leading up to 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) is similar to those in cholesterol synthesis; however, in ketone body synthesis, HMG CoA lyase (rather than HMG CoA reductase) is used (see Fig. 7-4).

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Jun 18, 2016 | Posted by in BIOCHEMISTRY | Comments Off on Lipid Metabolism

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