Lipids are transported in the blood via lipoproteins such as VLDL, LDL, HDL, and chylomicrons.

Chylomicrons (from the small intestine) shuttle ingested TGs to the capillaries of muscle and adipose to be degraded by lipoprotein lipase (LPL).

VLDL (from the liver) shuttle endogenous lipids to LPL and can be converted to IDL.

HDL (from the liver) transports Apo to chylomicrons and VLDL; and picks cholesterol from peripheral tissues to return to the liver for processing.

LDL form from LPL-degraded VLDL and shuttle lipids to the peripheral tissues.

Synthesis of FA occurs when there excess glucose (like after a meal).

1) Citrate exits TCA via shuttle to cytosol, where it's converted back to Acetyl-CoA.

2) Biotin (acetyl CoA carboxylase) catalyzes the rate-limiting conversion to malonyl CoA. This step is activated by CO2.

3) NADPH is used for Fatty acid synthase to make palmitate. Elongation and desaturation occurs in the ER.

TAG are synthesized in the liver from glycerol-3-phosphate and FA. Glycerol is provided to the liver as a by-product of LPL action in muscle and adipose.

TAG is packaged with VLDL in the liver to be transported to the capillaries where it can be degraded by LPL or stored in adipose tissue.

KB synthesis occurs in liver mitochondria when acetyl CoA accumulates; and thus never occurs when the body needs ATP.

The main ketone bodies are acetoacetate and beta-hydroxybutarate, which are transported to the muscle cells where they are immediately metabolized, under normal conditions.

Glutamine and Alanine are the major intertissue AA. Function primarily to transport NH3 to the kidneys for removal as urea. Also can be sent to liver for metabolism.

At any time, Glu is produced from protein degradation or TCA (alpha-ketoglutarate). Ala is produced from protein degradation or pyruvate. These conversions are catalyzed by aminotransferases.

Cells need to maintain a constant AA pool in order to carry out:

- protein synthesis

- gluconeogensis (liver)

- AA metabolism

- synthesis of nucleotides (nervous system)

Cells accomplish this by:

1) protein degradation

2) dietary protein intake

3) De-novo synthesis

Skeletal muscle is the primary source of AA metabolism. It is the site of protein degradation during periods of fasting and hypercatabolic state.

PVT TIM HALL

Phenylalanine

Valine

Tryptophan

Threonine

Isoleucine

Methionine

Histidine

Arginine

Leucine

Lysine

Arginine is only essential during growth

Tyrosine is only essential in Phe deficiency or PKU

Asparagine is essential for cancer cells, i.e. converted to Aspartic acid may prevent tumor formation

Almost all AA are gluconeogenic

Leucine and Lysine are only ketogenic

Tryptophan, Tyrosine, Isoleucine & Phenylalanine are both

Ammonia is toxic to cells. Usually, it is packaged in non-toxic Urea by the liver (from Glu and Ala) and sent to the kidneys for disposal.

A defect in the Urea cycle can lead to hyperammonia, which most affects the CNS. NH3 can disrupt TCA by converting alpha-ketoglutarate to Glu.

1) EtOH is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) in the cytosol, which begins in the stomach, but occurs primarily in the liver (much higher affinity).

2) Acetaldehyde is oxidized to acetate by aldehyde dehydrogenase in the liver mitochondria.

3) Acetate is released to the blood, where it is picked up by tissues and converted to acetyl-CoA by acetyl-CoA synthetase.

Regulation of ADH activity:

- inhibited by Fomepizole and NADH

- produced less in women and degraded during fasting = get drunk quicker

Regulation of ALDH activity:

- inhibited by Disulfiram = get drunk quicker

- some Asians produce much less ALDH = get drunk quicker

MEOS is part of cytochrome p450 in smooth ER.

Regulation of CYP2E1 activity:

- only contributes to 10% of normal metabolism

- high affinity for EtOH

- much more active in alcoholics

- leads to ROS production

Oxidation of ethanol leads to an increase ratio of NADH to NAD+

- NAD+ needed for carbohydrate metabolism

- acetyl-CoA build-up

- activation of lipogenesis and ketogenesis

- inhibition of:

• lipid metabolism
• pyruvate dehydrogenase (TCA)
• gluconeogenesis

The body uses three main substrates to coordinate metabolic homeostasis:

- carbohydrates (glucose)

- protein (AA)

- fat (TG)

The goal is to maintain a relatively constant serum glucose level while also delivering enough energy needed for cellular activity. This is accomplished by:

- glycolysis (cytosol), ox. phos (mitochondria), and glycogenolysis and gluconeogenesis (liver)

- protein storage and degradation in muscle

- lipogenesis, lipid metabolism, and lipid storage in adipose

Insulin is released in response to increased levels of glucose. Therefore it has the following metabolic effects:

(-) glycogenolysis

(-) gluconeogenesis

(-) ketogenesis

(-) lipolysis

And enzymatic effects:

(+) phosphofructokinase-2 (PFK-2)

(+) pyruvate kinase

(+) pyruvate dehydrogenase

(+) acetyl CoA carboxylase

(-) glycogen phosphorylase

(-) phosphorylase kinase

Glucagon is released in response to low glucose levels. Thus, it has the following effects:

(+) glycogenolysis

(+) gluconeogenesis

(+) ketogenesis

(+) lipolysis

And enzymatic effects:

(+) glycogen phosphorylase

(+) PFK-2 phosphatase

(+) phosphorylase kinase

(-) acetyl CoA carboxylase

(-) pyruvate kinase

(-) pyruvate dehydrogenase

(-) glycogen synthase

The body uses a cascade of fuel sources as it enters starvation. The relative order is:

1) Glucose in tissue

2) Glycogen from liver

3) Lipids from adipose tissue

4) Amino acids from muscle

5) Ketone bodies from liver

Not all tissues can metabolize all fuels:

- The brain uses more KB and less glucose during starvation

- RBCs can only use glucose

- Most other tissues use FA during starvation

Energy in > Energy out

(1) excess TAG stored in adipose tissue = obesity

(2) chronic hyperglycemia causes progressive insulin resistance (diabetes mellitus)

(3) increase in TG leads to increase in LDL and decrease in HDL = athersclerosis and increasing risk for heart defects