Biochemistry of Ketone Bodies and Cholesterol

Cholesterol controls the flexibility of cell membranes.

Plasma lipoproteins carry cholesterol in two forms: free cholesterol in the outer layer and cholesterol esters inside the core.

Vitamin D3 is made from cholesterol through a series of steps involving sunlight exposure.

All steroid hormones (like testosterone, estrogen, and cortisol) are derived from cholesterol.

Bile acids, which help digest fat, are produced from cholesterol.

An excess of ketone bodies in the blood, leading to a decrease in pH.

A condition characterized by high levels of ketone bodies in the blood, resulting in metabolic acidosis.

The process of producing ketone bodies from fatty acids.

A diet high in fat and low in carbohydrates, which forces the body to burn fat for fuel, resulting in the production of ketone bodies.

The physiological state of producing ketone bodies as a result of a ketogenic diet, with a normal pH level.

An enzyme that catalyzes the rate-limiting step in cholesterol synthesis.

The active, dephosphorylated form of HMG-CoA reductase is stimulated by insulin, while the inactive, phosphorylated form is inhibited by glucagon.

Cholesterol acts as an allosteric inhibitor of HMG-CoA reductase, reducing its activity when cholesterol levels are high.

AMP-activated protein kinase (AMPK) is activated during periods of low energy availability, leading to the phosphorylation and inactivation of HMG-CoA reductase.

Statins are drugs that competitively inhibit HMG-CoA reductase, preventing cholesterol synthesis and lowering plasma cholesterol levels.

The enzyme that converts acetyl-CoA to malonyl-CoA, a key step in fatty acid synthesis. It exists in two forms: active (dephosphorylated) and inactive (phosphorylated).

This pathway converts excess glucose into fatty acids and ultimately triglycerides (TAG) during carbohydrate feeding.

Hormones like glucagon and epinephrine inhibit ACC, ultimately reducing fatty acid synthesis.

A system within the endoplasmic reticulum that elongates fatty acids by adding 2-carbon units from malonyl-CoA. It requires NADPH as a hydrogen donor, similar to de novo synthesis. However, it can only elongate existing fatty acids (C10-24) and cannot initiate de novo synthesis.

These fatty acids include linoleic acid (omega-6) and linolenic acid (omega-3) and they are essential because our bodies cannot synthesize them. They are required in our diet.

The availability of oxaloacetate, a molecule involved in the TCA cycle, controls the rate of ketolysis.

Ketone bodies are an important alternate energy source during starvation.

Ketogenesis, the process of making ketone bodies, is a preparatory step for the liver to fully oxidize fatty acids.

An enzyme that catalyzes the conversion of glycerol to glycerol-3-phosphate. This process is crucial for triglyceride synthesis in the liver, kidneys, and intestinal mucosal cells.

A molecule formed from glycerol and three fatty acids. It is the major form of energy storage in the body, found primarily in adipose tissue.

A molecule produced during glycolysis, which serves as a precursor for glycerol-3-phosphate synthesis in adipose tissue. It is converted to glycerol-3-phosphate by a different pathway than in other tissues.

The process of attaching fatty acids to glycerol-3-phosphate to form triacylglycerol. This process is essential for the storage of excess energy in the form of fat.

An intermediate in triacylglycerol synthesis that is formed by attaching two fatty acids to glycerol-3-phosphate. It is further converted to triacylglycerol by adding another fatty acid.

Ketogenesis is the body's process of producing ketone bodies (like acetoacetate and β-hydroxybutyrate) from fatty acids. This happens when the body's primary fuel source, glucose, is scarce, such as during starvation or uncontrolled diabetes.

When glucose is scarce, the body switches to utilizing fatty acids as fuel. This leads to increased fatty acid oxidation, generating an abundance of acetyl-CoA. However, without sufficient glucose, the Krebs cycle slows down, causing a buildup of acetyl-CoA. The liver then transforms this excess acetyl-CoA into ketone bodies.

Ketolysis is the metabolic process where the body breaks down ketone bodies into usable energy. This occurs primarily in extrahepatic tissues (tissues other than the liver), as the liver lacks a key enzyme needed for this process.

The breakdown of ketone bodies requires the participation of the Krebs cycle (also known as the citric acid cycle). One essential component of this process is the enzyme thiophorase, which relies on succinyl-CoA provided by the Krebs cycle. This makes the functioning of the Krebs cycle crucial for ketolysis.

β-hydroxybutyrate, a ketone body, is converted into acetoacetate, which then produces two molecules of acetyl-CoA. This acetyl-CoA can then enter the Krebs cycle for final energy generation.

The liver is the primary site where ketone bodies are produced due to the presence of the enzymes HMG-CoA synthase and HMG-CoA lyase.

Acetoacetyl-CoA, β-hydroxybutyrate, and acetone are the three main ketone bodies.

Ketone bodies are transported to other tissues, like muscles, and used as an alternative energy source when glucose is not readily available.

Ketogenesis primarily utilizes acetyl-CoA from fatty acid oxidation because carbohydrates produce pyruvate, which generates oxaloacetate.

HMG-CoA synthase and HMG-CoA lyase are crucial enzymes in the process.

In certain situations like prolonged fasting or a low-carbohydrate diet, the body relies on ketone bodies for energy.

The process of breaking down fatty acids by removing two-carbon units at a time, starting from the carboxyl end.

A rare genetic disorder caused by a deficiency of α-hydroxylase, leading to the accumulation of phytanic acid in the body.

The process of synthesizing new fatty acids from acetyl-CoA units, primarily in the liver and lactating mammary gland.

A molecule that regulates the rate-limiting step in cholesterol synthesis, which is catalyzed by HMG-CoA reductase.

Acetyl-CoA, produced in the mitochondria, cannot directly cross into the cytosol for fatty acid synthesis. It combines with oxaloacetate to form citrate, which is then transported out. In the cytosol, citrate is broken back down to regenerate acetyl-CoA.

This enzyme catalyzes the first committed step in fatty acid synthesis by converting acetyl-CoA to malonyl-CoA, a vital 2-carbon building block. It is regulated by hormones and cellular energy levels.

This large multi-enzyme complex, located in the cytosol, is responsible for synthesizing palmitic acid (a 16-carbon saturated fatty acid) from acetyl-CoA units. It also utilizes NADPH for the process.

The pentose phosphate pathway (HMP), malic enzyme, and cytosolic isocitrate dehydrogenase (DH) all contribute to the production of NADPH, which is essential for fatty acid synthesis.

Malonyl-CoA, the product of acetyl-CoA carboxylase (ACC), inhibits carnitine palmitoyltransferase I (CPT I), preventing fatty acids from entering the mitochondria for breakdown. This creates a balance between fatty acid synthesis and breakdown.