OM 1012 – Lipid Mobilization and Catabolism (VOCABULARY Flashcards)

Vocabulary flashcards covering fatty acid transport, oxidation, regulatory enzymes, ketogenesis/ketolysis, peroxisomal pathways, and related disorders from the lecture notes.

Beta-oxidation

A major catabolic pathway occurring in the mitochondrial matrix that systematically shortens fatty acyl-CoA molecules by two-carbon units with each cycle, producing acetyl-CoA, NADH, and FADH_2. This process is the primary way fatty acids are broken down for energy.

Carnitine shuttle

A crucial transport system responsible for moving long-chain acyl groups from fatty acids into the mitochondrial matrix, where beta-oxidation takes place. It involves three key components: CPT-I, carnitine, and CPT-II. This shuttle is the rate-limiting step for the entry of long-chain fatty acids into mitochondria for oxidation.

CPT-I (carnitine palmitoyltransferase I)

An enzyme located on the outer mitochondrial membrane. It catalyzes the transfer of the acyl group from acyl-CoA to carnitine, forming acylcarnitine which can then cross the inner mitochondrial membrane. CPT-I is inhibited by malonyl-CoA, effectively gating the entry of long-chain fatty acids (LCFAs) into the mitochondria for oxidation.

CPT-II (carnitine palmitoyltransferase II)

An enzyme located on the inner mitochondrial membrane, facing the matrix. It transfers the acyl group from acylcarnitine back to CoA, regenerating acyl-CoA inside the mitochondrial matrix for beta-oxidation and simultaneously releasing free carnitine, which then returns to the intermembrane space.

Malonyl-CoA

A molecule that serves as a key regulator of fatty acid oxidation. It inhibits CPT-I, thereby preventing long-chain fatty acids (LCFAs) from entering the mitochondria. High levels of malonyl-CoA signal energy sufficiency (from carbohydrate metabolism via acetyl-CoA carboxylase activity), ensuring that fatty acid synthesis is prioritized while fatty acid breakdown is decreased.

Acetyl-CoA

A two-carbon molecule produced as the end product of beta-oxidation. It can enter the TCA (Krebs) cycle for complete oxidation to generate ATP or be used as a precursor for ketogenesis. In the liver, acetyl-CoA cannot exit the mitochondria directly and, when abundant, allosterically activates pyruvate carboxylase, promoting gluconeogenesis during fasting states.

Pyruvate carboxylase

A mitochondrial enzyme that catalyzes the anaplerotic reaction converting pyruvate to oxaloacetate. It is allosterically activated by high levels of acetyl-CoA, particularly relevant during fasting when gluconeogenesis is essential to maintain blood glucose levels for the brain and other tissues.

HMG-CoA synthase

A key enzyme in ketogenesis, primarily found in liver mitochondria. It combines two molecules of acetyl-CoA (actually, acetyl-CoA and acetoacetyl-CoA) to form 3-hydroxy--3-methylglutaryl-CoA (HMG-CoA). This reaction is considered the rate-limiting step of ketone body synthesis.

HMG-CoA lyase

An enzyme involved in ketogenesis, acting after HMG-CoA synthase. It cleaves HMG-CoA into acetoacetate (a ketone body) and acetyl-CoA, playing a critical role in the final stages of ketone body formation in the liver.

Ketone bodies

Water-soluble fuel molecules — namely acetoacetate, 3-hydroxybutyrate, and acetone — produced by the liver, especially during prolonged fasting or starvation, from excess acetyl-CoA when the TCA cycle is overwhelmed or less active. They serve as an alternative energy source for peripheral tissues, including the brain, heart, and skeletal muscle.

Acetoacetate

One of the primary ketone bodies. It can be directly utilized by peripheral tissues after activation to acetoacetyl-CoA, or it can be non-enzymatically decarboxylated to acetone, or enzymatically reduced to 3-hydroxybutyrate. It is a major circulating form of ketone body.

3-Hydroxybutyrate (β-hydroxybutyrate)

The most abundant and major circulating ketone body during fasting. It is formed from acetoacetate in a reversible reaction requiring NADH. It is transported in the blood to extrahepatic tissues for energy production.

Acetone

A volatile ketone body produced via the spontaneous, non-enzymatic decarboxylation of acetoacetate. Unlike acetoacetate and 3-hydroxybutyrate, acetone is not used for energy generation in the body and is primarily exhaled, contributing to the characteristic 'fruity' breath observed in conditions like diabetic ketoacidosis.

Ketogenesis

The metabolic process of producing ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone) from acetyl-CoA, primarily in the mitochondria of liver cells. This process is upregulated during periods of prolonged fasting, starvation, or uncontrolled diabetes, when fatty acid oxidation is high and oxaloacetate levels are limiting the TCA cycle.

Ketolysis

The metabolic pathway by which extrahepatic tissues (tissues other than the liver) utilize ketone bodies for energy. This process involves converting ketone bodies back into acetyl-CoA, which can then enter the TCA cycle for ATP production. The liver cannot perform ketolysis as it lacks the necessary enzyme, beta-ketoacyl-CoA transferase (thiophorase).

Glycerol fate after TAG lipolysis

Following the breakdown of triglycerides (TAGs) in adipose tissue, glycerol is released into the bloodstream due to its water-soluble nature. It is then primarily taken up by the liver, where it is phosphorylated to glycerol--3-phosphate and subsequently converted to dihydroxyacetone phosphate (DHAP), an intermediate of glycolysis and gluconeogenesis, thereby feeding into glucose production.

Triglycerides (TGL)

The most common form of fat in the body and the main constituents of natural fats and oils. They are esters formed from one glycerol molecule and three fatty acid molecules. Triglycerides serve as the primary storage form of energy in adipose tissue and can be lipolyzed to release free fatty acids and glycerol.

Hormone-sensitive lipase (HSL)

A key enzyme found in adipose tissue that catalyzes the hydrolysis (cleavage) of triglycerides (TAGs) into free fatty acids and glycerol. Its activity is highly regulated: it is activated by counter-regulatory hormones such as cortisol, epinephrine, norepinephrine, and glucagon (via cAMP-dependent phosphorylation), and strongly inhibited by insulin.

Short-chain fatty acids (SCFAs)

Fatty acids containing fewer than 6 carbon atoms. They are primarily produced by gut bacteria through the fermentation of dietary fiber. SCFAs can be absorbed directly into the portal blood without requiring the carnitine shuttle and serve as important energy substrates for enterocytes (colon cells) and the liver.

Medium-chain fatty acids (MCFAs)

Fatty acids containing 6 to 12 carbon atoms. Unlike LCFAs, MCFAs do not require carnitine-dependent transport to enter the mitochondrial matrix for beta-oxidation, making their oxidation more rapid. They are commonly found in milk and coconut oil and are often used as easily digestible energy sources.

Long-chain fatty acids (LCFAs)

Fatty acids containing 12 to 18 carbon atoms. These are the most common fatty acids in the diet and in storage. They critically require the carnitine shuttle system (CPT-I and CPT-II) for transport into the mitochondrial matrix to undergo beta-oxidation. LCFAs represent a major energy source, particularly during sustained physical activity and fasting.

Very long-chain fatty acids (VLCFAs)

Fatty acids containing 22 or more carbon atoms. These large fatty acids are primarily oxidized in peroxisomes, not mitochondria. Their initial activation and several rounds of beta-oxidation occur within peroxisomes, which do not generate immediate ATP, contrasting with mitochondrial beta-oxidation.

Peroxisomal beta-oxidation

A specialized pathway for the oxidation of very long-chain fatty acids (VLCFAs) and some branched-chain fatty acids, occurring in peroxisomes. The initial dehydrogenation step in peroxisomes generates hydrogen peroxide (H2O2), rather than FADH_2 and ATP. This pathway shortens VLCFAs until they become medium- or short-chain fatty acids, which are then transferred to mitochondria for complete oxidation.

Alpha-oxidation

A minor fatty acid oxidation pathway, primarily occurring in peroxisomes. It removes one carbon atom from the \alpha (alpha) carbon when beta-oxidation is blocked by a methyl group on the \beta (beta) carbon, such as in phytanic acid. This pathway allows for the breakdown of branched-chain fatty acids, particularly in the brain and for phytanic acid metabolism.

Omega-oxidation

A minor fatty acid oxidation pathway that occurs in the endoplasmic reticulum and peroxisomes. Instead of acting at the beta-carbon, it oxidizes the \omega (omega) carbon (the methyl carbon furthest from the carboxyl group). This process converts fatty acids into dicarboxylic acids and can be upregulated when beta-oxidation is defective, serving as an alternative minor pathway.

Phytanic acid

A branched-chain fatty acid derived from the diet (e.g., from chlorophyll). Due to its branch at the \beta carbon, it cannot undergo conventional beta-oxidation. Instead, it requires initial processing via alpha-oxidation. A deficiency in the enzyme responsible for its alpha-oxidation (Phytanoyl-CoA \alpha-hydroxylase, PhyH) leads to Refsum disease.

Omega-oxidation products

The primary products of omega-oxidation are dicarboxylic acids (DCAs), which have a carboxyl group at both ends of the molecule. These DCAs can then be channeled into the beta-oxidation pathways (typically mitochondrial) to be further shortened and ultimately metabolized for energy.

Zellweger syndrome

A severe, autosomal recessive peroxisomal biogenesis disorder characterized by the absence or dysfunction of peroxisomes. This defect leads to the systemic accumulation of very long-chain fatty acids (VLCFAs) and branched-chain fatty acids. It results in profound neurological dysfunction, developmental delays, and typically early death.

Refsum disease

An autosomal recessive inherited metabolic disorder caused by a deficiency in the peroxisomal enzyme phytanoyl-CoA \alpha-hydroxylase (PhyH). This enzyme is crucial for the alpha-oxidation of phytanic acid. Its deficiency leads to the accumulation of phytanic acid in tissues, causing progressive neurological symptoms, including retinitis pigmentosa, peripheral neuropathy, and cerebellar ataxia. Dietary restriction of phytanic acid can help manage the condition.

X-linked adrenoleukodystrophy (X-ALD)

A peroxisomal disorder inherited in an X-linked recessive pattern. It is caused by a defect in the ABCD1 gene, which encodes a peroxisomal membrane protein involved in the transport of very long-chain fatty acids (VLCFAs) into the peroxisome for degradation. This leads to the accumulation of VLCFAs in the brain, spinal cord, and adrenal glands, resulting in progressive neurologic dysfunction and adrenal insufficiency.

Glycerol-3-phosphate (DHAP) pathway

This pathway describes the metabolic conversion of glycerol, released from triglyceride breakdown, primarily within the liver. Glycerol is phosphorylated to glycerol--3-phosphate, which is then oxidized to dihydroxyacetone phosphate (DHAP). DHAP is a key intermediate that can feed directly into gluconeogenesis (to synthesize glucose) or glycolysis, connecting fat metabolism to carbohydrate metabolism.

Activation energy of fatty acids

Before fatty acids can undergo beta-oxidation, they must first be activated by conversion to fatty acyl-CoA. This activation step requires the expenditure of 2 ATP equivalents per fatty acid molecule, specifically involving the hydrolysis of ATP to AMP and pyrophosphate (PPi). This energy investment ensures the fatty acid is ready for subsequent metabolic reactions.

Diabetic ketoacidosis (DKA)

A life-threatening metabolic emergency that most commonly occurs in individuals with Type 1 diabetes due to a severe absolute or relative deficiency of insulin. This leads to unchecked lipolysis and excessive production of ketone bodies (ketogenesis) in the liver, overwhelming the body's buffering capacity and causing metabolic acidosis. Symptoms include high blood glucose, dehydration, electrolyte imbalance, deep rapid breathing (Kussmaul respirations), and typical 'fruity' breath due to acetone.