Lipid Metabolism

Lipid metabolism encompasses the intricate processes that occur within cells, involving the synthesis, breakdown, and storage of fats. After digestion and absorption, fatty acids are transported and packaged for use. Key processes include lipogenesis (synthesis), lipolysis (breakdown), and beta oxidation (energy production). Cholesterol is also part of lipid metabolism. Animals utilize both dietary fats and stored fat for energy and cellular function. Lipids are digested by lipase enzymes in the gastrointestinal tract, aided by bile acids, and are absorbed directly through cell membranes. Overall, lipid metabolism plays a crucial role in energy utilization, structural component production, and maintaining cellular homeostasis. In this article we will study β-Oxidation of saturated fatty acid using Palmitic acid as an example.

β-Oxidation of saturated fatty acid

β-Oxidation is a repetitive four-step metabolic process by which long-chain fatty acids convert into two-carbon compounds (acetyl CoA). These fatty acids, being insoluble in water and chemically inert, serve as perfect storage fuels. However, their catabolism presents challenges due to their properties. The process occurs in the mitochondria and involves successive oxidations of the β-carbon, resulting in the removal of two carbon atoms from the carboxyl end of the fatty acyl-CoA. Overall, β-oxidation efficiently utilizes fats for energy production.

Process Overview

β-Oxidation occurs primarily in the mitochondria of eukaryotic cells.
It involves the sequential breakdown of saturated fatty acids into smaller units.
The end product is acetyl-CoA, which enters the citric acid cycle (Krebs cycle) for energy production.
The name “β-oxidation” comes from the fact that the beta carbon of the fatty acid chain undergoes oxidation, leading to the formation of a carbonyl group, and the cycle repeats.

Steps in β-Oxidation

Each cycle of β-oxidation consists of four enzymatic reactions:

Oxidation: The β carbon is oxidized, producing FADH₂.
Hydration: A water molecule is added.
Second Oxidation: Another oxidation step yields NADH + H⁺.
Thiolytic Cleavage: An acetyl-CoA molecule is released, leaving behind an acyl-CoA with two fewer carbon atoms.

Energy Production

β-Oxidation provides a crucial energy source by breaking down fatty acids. Acetyl-CoA feeds into the citric acid cycle, generating NADH and FADH₂ for the electron transport chain.

β-Oxidation of palmitic acid

β-oxidation efficiently breaks down palmitic acid into acetyl CoA, providing a vital energy source for cells. This process is explained below.

Activation of Fatty Acid

Palmitic acid (16 carbons) is first converted to palmitoyl CoA by an enzyme called thiokinase or fatty acyl CoA synthetase.
This activation step occurs in the cytoplasm and requires ATP and Mg²⁺.

Transport into Mitochondria

The inner mitochondrial membrane does not allow fatty acids to pass through directly.
Palmitoyl CoA enters the mitochondria via the carnitine shuttle:
Fatty acyl CoA is transferred to carnitine, forming fatty acyl carnitine (catalyzed by carnitine acyl transferase I on the outer mitochondrial surface).
Acyl carnitine enters the mitochondrial matrix.
Inside the matrix, it is converted back to fatty acyl CoA by carnitine acyl transferase II (located in the inner mitochondrial membrane). Carnitine is released and returns to the cytosol for reuse.

β-Oxidation Cycle

Each cycle consists of four enzymatic reactions as follows.

Oxidation: An oxidation step produces FADH₂.
Hydration: Water is added across the double bond.
Second Oxidation: Another oxidation step generates NADH + H⁺.
Thiolytic Cleavage: A molecule of acetyl CoA is released.

Palmitic acid (16 carbons) undergoes 7 β-oxidation cycles. Each cycle yields 1 FADH₂, 1 NADH + H⁺, and 1 acetyl CoA.

Total ATP production from these products

Acetyl CoA enters the TCA cycle, releasing 12 ATP per acetyl CoA.
FADH₂ and NADH + H⁺ enter the electron transport chain, generating 2 ATP and 3 ATP, respectively.
Net ATP gain: 129 ATP (after accounting for the initial ATP used during activation).

Unsaturated Fatty Acids

Monounsaturated fatty acids (with a double bond) follow similar steps, requiring an extra enzyme called enoyl CoA isomerase. Polyunsaturated fatty acids (with multiple double bonds) need additional enzymes: enoyl CoA isomerase and 2,4-dienoyl CoA reductase.

Ketoacidosis

Ketoacidosis is a serious complication of diabetes that can be life-threatening.

Cause: It occurs when the body can’t produce enough insulin. Insulin helps sugar (glucose) enter cells, providing energy. Without enough insulin, the body breaks down fat for fuel, leading to the production of ketones (acids) in the bloodstream.

Symptoms

Early Signs: These may develop quickly, sometimes within 24 hours. They include excessive thirst, frequent urination, nausea, vomiting, stomach pain, weakness, and fruity-scented breath.
More Certain Signs: Home blood and urine test kits can detect high blood sugar levels and ketone levels in urine.

When to Seek Help

Contact Your Health Care Provider if,

You’re vomiting and can’t keep down food or liquid.
Your blood sugar level is higher than your target range and doesn’t respond to home treatment.
Your urine ketone level is moderate or high.

Seek Emergency Care if

Your blood sugar level exceeds 300 mg/dL (16.7 mmol/L) for more than one test.
You have ketones in your urine and can’t reach your health care provider.
You experience severe symptoms like confusion, shortness of breath, or weakness.

Ketone Bodies

Ketone bodies, also known simply as ketones, are substances produced by the liver during a process called gluconeogenesis. This process occurs when glucose levels are low, such as during fasting or starvation. Ketone bodies play a crucial role in energy metabolism, especially during times of low carbohydrate availability. They allow our bodies to adapt and survive when glucose is scarce.

There are three main ketone bodies,

Acetoacetate
Beta-hydroxybutyrate
Acetone

Formation of Ketone Bodies (Ketogenesis)

When you fast or experience prolonged periods without food, your body transitions from the absorptive state (where it stores excess glucose as fats and proteins) to the postabsorptive state.

In the postabsorptive state,

The liver converts fatty acids, glycogen, and even amino acids into glucose through gluconeogenesis.
As glycogen stores become depleted, the liver produces ketone bodies alongside glucose.
These ketone bodies serve as an alternative energy source when glucose is scarce.
Gluconeogenesis also produces acetoacetate and beta-hydroxybutyrate, which are released into the bloodstream to feed the brain.
The muscles and other organs primarily switch to using fatty acids for energy, conserving glucose for the brain (a process called glucose sparing).

Utilization of Ketone Bodies

Extrahepatic tissues (tissues outside the liver) continuously utilize ketone bodies.
The brain, however, prefers glucose but can switch to ketone bodies after about 4 days of starvation.
Ketone bodies provide an extended energy source, allowing organisms to survive longer without food.

Negative Side-Effects

If ketone bodies are produced at a high rate (due to prolonged fasting or uncontrolled diabetes), they can overwhelm the kidneys. Excessive ketone bodies can lead to acidosis, lowering blood pH and affecting bodily functions.

De novo synthesis of fatty acids

De novo synthesis refers to the process by which circulation-derived carbohydrates are transformed into fatty acids. These fatty acids can then be further converted into triglycerides or other lipids. This process primarily occurs in the cytosol of various tissues, including the mammary gland, adipose tissues, and liver.

Key Steps in Fatty Acid Biosynthesis

Malonyl-CoA Production: The first critical step involves the production of malonyl-CoA. Acetyl-CoA is carboxylated to form malonyl-CoA in the presence of ATP and the enzyme acetyl-CoA carboxylase. Bicarbonate serves as the source of CO₂ for this reaction. Malonyl-CoA is crucial for controlling the synthesis of fatty acids.

Fatty Acid Synthase (FAS) Complex: The FAS enzyme complex produces fatty acids following the synthesis of malonyl-CoA.

This multienzyme polypeptide complex includes the acyl carrier protein (ACP) and links the individual enzymes necessary for fatty acid synthesis. The complex also involves 4′-phosphopantetheine, a form of the vitamin pantothenic acid.

Chain Elongation: The series of reactions repeats several times:

A cysteine (-SH group) joins with an acetyl-CoA priming molecule, while malonyl-CoA joins with the -SH group next to it on the 4′-phosphopantetheine of ACP in the other monomer.
Malonyl acetyl transacylase catalyzes these reactions, forming the acetyl (acyl)-malonyl enzyme.
The acetyl group attacks the methylene group of the malonyl residue, releasing CO₂ to create the 3-ketoacyl enzyme.
Decarboxylation enables the reaction to proceed, moving the entire chain of reactions forward.
The process repeats until a saturated 16-carbon acyl radical (palmitoyl) is formed.

De Novo Synthesis of Palmitic Acid

De novo lipogenesis refers to the creation of fatty acids from acetyl-CoA, which marks the beginning of this pathway.

Formation of Malonyl-CoA

Malonyl-CoA, a 3-carbon compound, is initially produced by removing an acetyl-CoA molecule from the mitochondria.
When malonyl-CoA combines with another acetyl-CoA, it forms an acetyl-CoA-malonic acid complex.

Building Palmitic Acid (16-Carbon Fatty Acid)

Through a series of similar reactions, 2 carbons are added to the growing chain of carbons 7 times.
The end result is a 16-carbon fatty acid, specifically palmitic acid.
This process occurs in three major sites:
- Adipose tissue
- Liver
- Kidneys

Key Stages in De Novo Synthesis

Production of NADPH and Acetyl CoA

Acetyl CoA is essential for fatty acid production.
Sources of Acetyl CoA include pyruvate, which is oxidized in the mitochondrial matrix, as well as amino acids and ketone bodies.
Since Acetyl CoA cannot directly penetrate mitochondrial membranes, it is transported as oxaloacetate, which is then converted back to Acetyl CoA.

Conversion to Malonyl CoA from Acetyl CoA

Malonyl CoA is formed by carboxylating acetyl CoA.
This ATP-dependent reaction requires biotin for CO₂ fixation.

Reactions of Fatty Acid Synthase Complex

The fatty acid synthase (FAS) complex, a multifunctional enzyme, catalyzes the reactions.
Each monomer contains acyl carrier proteins (ACPs) and enzymes.
The sequence of reactions leads to the formation of palmitate.

Palmitate (palmitic acid) contains 16 carbon atoms. 2 carbons come from Acetyl CoA, while the remaining 14 carbons come from Malonyl CoA. The overall reaction can be summarized as:

CH₃CO-S-CoA (Acetyl CoA) + 7HOOCCHCO-S-CoA (7 Malonyl CoA) + 14NADPH + 14H⁺ → CH₃(CH₂)₁₄COOH (Palmitate) + 7CO₂ + 6H₂O + 8CoA-SH + 14NADP⁺

Cholesterol

Cholesterol is a waxy substance found throughout the body. It’s essential for good health, but too much of the bad kind can increase your risk of heart disease or stroke. Cholesterol is a fat-like substance that circulates in your blood. It’s not inherently bad; your body needs it for several vital functions. Cholesterol is used to

Build cell membranes.
Create hormones (such as estrogen and testosterone).
Synthesize vitamin D.

Your liver produces all the cholesterol your body requires.

Sources of Cholesterol

Endogenous Cholesterol: Your liver makes cholesterol, ensuring you have enough for essential processes.
Exogenous Cholesterol: Comes from dietary sources, primarily animal-based foods like meat, poultry, and dairy products. Some tropical oils (like palm oil and coconut oil) also contain saturated fats that can raise cholesterol levels.

Types of Cholesterol

LDL (Low-Density Lipoprotein): Known as “bad” cholesterol. High LDL levels can lead to cholesterol buildup in artery walls, increasing the risk of heart disease.
HDL (High-Density Lipoprotein): Known as “good” cholesterol. HDL helps remove excess cholesterol from the bloodstream, reducing the risk of heart disease.

As cholesterol levels rise, so does the risk to your health. High cholesterol contributes to conditions like atherosclerosis, where cholesterol deposits narrow and harden arteries. Atherosclerosis can lead to blood clots, heart attacks, and strokes. Remember the three Cs: Check, Change, and Control. Regular cholesterol checks, lifestyle adjustments, and professional guidance are crucial for maintaining heart health.

Biological significance of cholesterol

Cholesterol plays a crucial role in various biological processes within the body. Let’s explore its significance:

Cell Membrane Integrity: Cholesterol is a vital component of cell membranes. It helps maintain their fluidity, stability, and integrity. By interspersing between phospholipids, cholesterol ensures that cell membranes remain flexible yet resistant to extreme changes in temperature and pressure.
Hormone Synthesis: Cholesterol serves as a precursor for the biosynthesis of steroid hormones. These hormones include estrogen, testosterone, progesterone, and cortisol. Without cholesterol, our bodies wouldn’t be able to produce these essential hormones.
Bile Acid Production: Cholesterol is involved in the synthesis of bile acids in the liver. Bile acids play a crucial role in digestion by emulsifying fats and aiding their absorption in the small intestine. Bile acids also help eliminate waste products from the liver.
Vitamin D Synthesis: To create vitamin D, intermediates of cholesterol biosynthesis must be present. When our skin is exposed to sunlight, cholesterol derivatives are converted into vitamin D. Vitamin D is essential for calcium absorption, bone health, and immune function.
Atherosclerosis and Cardiovascular Risk: Elevated levels of cholesterol, especially when bound to low-density lipoprotein (LDL) (often referred to as “bad cholesterol”), may increase the risk of cardiovascular disease. Atherosclerosis, characterized by plaque buildup in arteries, can lead to heart attacks and strokes.

Conversion of cholesterol into bile acids

Cholesterol cannot be burned or decomposed directly in our body. Instead, it must be transformed into bile acids in the liver. The conversion of cholesterol into bile acids is critical for cholesterol homeostasis and efficient digestion of dietary fats. Bile acids play a vital role in emulsifying lipids and facilitating their absorption.

Hepatocytes (liver cells) are responsible for synthesizing bile acids using cholesterol as the substrate. Bile acid synthesis involves several enzymatic reactions and can be classified into two main pathways as follows.

Classic Pathway

Cholesterol 7α-hydroxylase (CYP7A1) converts cholesterol to 7α-hydroxycholesterol (7α-HOC).
The sterol 12α-hydroxylase (CYP8B1) further converts the intermediate 7α-hydroxy-4 cholesten-3-one (C4) to 7α, 12α-dihydroxy-4-cholesten-3-one, eventually leading to the synthesis of cholic acid (CA).

Alternative (Acidic) Pathway

In this pathway, cholesterol is converted to cholic acid (CA) directly without the intermediate step of 7α-hydroxy-4 cholesten-3-one (C4).
The acidic pathway involves different enzymes and provides an alternative route for bile acid synthesis.

The cholesterol undergoes various reactions to form bile acid. Some of the major mechanisms are,

Enzymatic Reactions: Cholesterol undergoes a series of enzymatic reactions.
Hydroxylation: The side chain of cholesterol molecules is oxidized, introducing hydroxyl groups.
Formation of Bile Acids: These modified cholesterol derivatives become bile acids.
Solubilizing Fat: Bile acids are essential for solubilizing fats in the digestive process.
Secretion into Bile: Bile acids are then secreted into the gallbladder.
Facilitating Lipid Absorption: When stored in the gallbladder, bile acids are released into the upper small intestine, where they serve as solubilizers. They help absorb lipids (fats) and fat-soluble vitamins.

Functions of bile acid

Bile acids have classic physiological functions:

In the liver, they form mixed micelles with cholesterol and phospholipids, preventing cholesterol precipitation and bile acid damage to the bile duct epithelium.
In the small intestine, bile acids, along with phospholipids, form mixed micelles to emulsify dietary lipids and facilitate their absorption.

Beyond these functions, bile acids also act as signalling molecules:

They serve as endogenous ligands for several nuclear receptors and cell surface G protein-coupled receptors.
These bile acid-activated receptors regulate various cellular pathways in normal physiology and diseases.

Enterohepatic Circulation

Bile acids are not permanently lost. Instead, they are recycled through a process called enterohepatic circulation. After aiding in digestion, bile acids are reabsorbed in the small intestine and transported back to the liver for reuse.

Conversion of cholesterol into steroid hormone

Steroid hormones include essential molecules like cortisol, aldosterone, progesterone, estradiol, and testosterone. These hormones play critical roles in various physiological processes, including sexual differentiation, growth, and maturation.

The synthesis of steroid hormones from cholesterol involves multiple steps occurring primarily in specific tissues:

Adrenal Cortex: Here, cholesterol is converted into adrenal steroid hormones such as corticosterone, cortisol, and aldosterone.
Gonads (Testes and Ovaries): In the gonads, cholesterol is transformed into progesterone, estradiol, and testosterone.
Placenta: During pregnancy, the placenta also contributes to steroid hormone production.

Key Enzymes Involved

Cytochrome P450 Enzymes: These heme-containing proteins catalyze the hydroxylation and cleavage of the steroid substrate. They function as monooxygenases, utilizing reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the electron donor for the reduction of molecular oxygen.
Hydroxysteroid Dehydrogenases: These enzymes further modify steroid intermediates. For example, 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase play crucial roles in the biosynthesis of active steroid hormones.

Cholesterol is transported into the mitochondria by a protein called steroidogenic acute regulatory protein (StAR). Once inside, cholesterol is converted into pregnenolone, a key intermediate. Pregnenolone can then be further converted into different steroid hormones, including estrogen and testosterone.

Formation of vitamin D

Cholecalciferol, also known as vitamin D3, is synthesized in the skin from a precursor called 7-dehydrocholesterol. When your skin is exposed to ultraviolet B (UV-B) light from sunlight, 7-dehydrocholesterol undergoes a photochemical reaction. This reaction converts 7-dehydrocholesterol into cholecalciferol (vitamin D3).

Steps involved

Skin Exposure: UV-B light penetrates the skin.
Conversion: 7-dehydrocholesterol absorbs UV-B and undergoes a conformational change, transforming into cholecalciferol (vitamin D3).
Transport: Cholecalciferol is then transported to the liver.

Liver and Kidney Hydroxylation:

In the liver, cholecalciferol is hydroxylated to form 25-hydroxyvitamin D3 (calcidiol).
Further hydroxylation occurs in the kidneys, converting 25-hydroxyvitamin D3 to its biologically active form, 1,25-dihydroxyvitamin D3 (calcitriol).

Biological functions of vitamin D

Calcium Absorption: It promotes calcium absorption in the intestines, crucial for bone health.
Cardiovascular Function: It supports cardiovascular health.
Lung and Muscle Health: It helps maintain healthy lungs, airways, and muscle function.
Immune System: It aids in fighting infections.
Protection Against Cancer: Some evidence suggests a protective effect against certain cancers.

Deficiency and Health Risks

Insufficient vitamin D can lead to various conditions like,

Brittle Bones: Osteoporosis and osteomalacia.
Rickets in children.
Other Health Conditions: Depression, high blood pressure, type 2 diabetes, asthma, and even high cholesterol.

Disorders of lipid metabolism

When there are disorders in lipid metabolism, it can lead to various health problems. Many lipid disorders are inherited. For example, familial hypercholesterolemia (FH) occurs when high cholesterol runs in a family. FH affects an estimated 1 in 200–500 people worldwide and is more common in certain ethnic groups. Consuming foods high in saturated fats can cause high blood cholesterol and elevated levels of triglycerides. Lifestyle factors such as physical inactivity, smoking, and excessive alcohol consumption also contribute. Certain diseases (e.g., type 2 diabetes, hypothyroidism, chronic kidney diseases) increase the risk of lipid disorders. Some of the common lipid metabolism disorders are explained below.

Hypercholesterolemia

Hypercholesterolemia, commonly known as high cholesterol, refers to elevated levels of cholesterol in the blood. Cholesterol is a waxy substance produced by the liver and obtained from dietary sources. While our bodies need cholesterol for essential functions (such as building cell membranes and producing hormones), excessive levels can lead to health problems.

Here are some key points about hypercholesterolemia:

Types of Hypercholesterolemia

Genetic Hypercholesterolemia:

Less common and usually inherited.
Examples include familial hypercholesterolemia (FH).

Acquired Hypercholesterolemia:

More common and often related to lifestyle factors.
It affects many adults, especially those with poor dietary habits and sedentary lifestyles.

Symptoms

Hypercholesterolemia rarely causes noticeable symptoms on its own.
However, its complications can be severe, including heart disease, stroke, and peripheral artery disease.

Causes and Risk Factors

Controllable Factors

Diet high in saturated fats.
Lack of exercise.
Stress and hormonal imbalances.
Obesity or overweight.

Uncontrollable Factors

Genetics (FH is often due to multiple genes).
Side effects of certain medications.
Other medical conditions (e.g., diabetes, high blood pressure).

Complications

Uncontrolled hypercholesterolemia can lead to:

Atherosclerosis: Cholesterol deposits in artery walls.
Reduced blood flow to the heart and brain.
Increased risk of heart attacks and strokes.

Prevention and Treatment

Lifestyle modifications

Healthy Diet: Limit saturated fats, consume unsaturated fats, and increase fiber intake.
Exercise Regularly: Physical activity helps manage cholesterol levels.
Weight Management: Maintain a healthy weight.
Quit Smoking and limit alcohol consumption.
Medications: Statins, bile acid sequestrants, and other drugs may be prescribed to lower cholesterol levels.

Atherosclerosis

Atherosclerosis is a condition where the arteries become narrowed and hardened due to the buildup of plaque (fats, cholesterol, and other substances) in the artery walls. Managing atherosclerosis involves a healthy lifestyle and regular medical check-ups to prevent complications.

Plaque Buildup

Over time, fatty deposits accumulate within the inner lining of arteries.
These deposits, known as plaque, consist of cholesterol, inflammatory cells, and other substances.
Plaque gradually narrows the arteries, restricting blood flow.

Consequences

Atherosclerosis can affect various arteries, including those in the heart, brain, legs, and kidneys.
Coronary Arteries: Plaque buildup in coronary arteries can lead to coronary artery disease, potentially causing chest pain (angina) or heart attacks.
Carotid Arteries: Plaque in carotid arteries (located in the neck) may reduce blood flow to the brain, increasing the risk of strokes.
Peripheral Arteries: Narrowed arteries in the legs can cause peripheral artery disease, leading to leg pain during walking (claudication).

Risk Factors

High Cholesterol: Elevated levels of LDL (low-density lipoprotein) cholesterol contribute to plaque formation.
High Blood Pressure: Hypertension damages artery walls, promoting plaque buildup.
Smoking, Diabetes, and Obesity increase the risk.
Inflammation plays a role in plaque development.

Prevention and Treatment

Lifestyle modifications are crucial:

Healthy Diet: Reduce saturated fats, consume fruits, vegetables, and whole grains.
Exercise Regularly: Physical activity helps maintain arterial health.
Quit Smoking and manage stress.
Medications (such as statins) may be prescribed to lower cholesterol and prevent plaque progression.
In severe cases, procedures like angioplasty, stent placement, or bypass surgery may be necessary.

Nonalcoholic Fatty Liver Disease (NAFLD)

NAFLD refers to the accumulation of fat in the liver without excessive alcohol intake.
It is becoming more common, especially in Middle Eastern and Western nations, as the number of people with obesity rises.
NAFLD ranges in severity from hepatic steatosis (fatty liver) to a more severe form called nonalcoholic steatohepatitis (NASH).

Obesity and NAFLD

Obesity is a significant risk factor for NAFLD.
About one-third of U.S. adults have NAFLD, and it affects about 75% of people who carry excess weight and 90% of people with severe obesity.
The excess fat in the liver can lead to inflammation and damage over time.

Prevention and Management

Lifestyle modifications are crucial:
Healthy Diet: Reduce saturated fats, consume fruits, vegetables, and whole grains.
Exercise Regularly: Physical activity helps maintain liver health.
Weight Management: Maintaining a healthy weight reduces the risk of NAFLD.

Summary

Lipid metabolism involves the oxidation of fatty acids to generate energy or synthesize new lipids. Beta oxidation breaks down fatty acids into acetyl-CoA in mitochondria, while fatty acid synthesis occurs in the cytoplasm, building fatty acids from acetyl-CoA and malonyl-CoA. Ketoacidosis results from excessive ketone body accumulation, often linked to uncontrolled diabetes. Disorders include nonalcoholic fatty liver disease (NAFLD), associated with obesity and liver damage, and hypercholesterolemia, characterized by high blood cholesterol levels and increased cardiovascular risk. Understanding these processes is crucial for overall health.