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← Electron Transport & ATP Synthesis/Lipid Metabolism

19. Lipid Metabolism

Reading time: ~45 minutes | Key topics: Beta-oxidation, carnitine shuttle, ketogenesis, fatty acid synthesis, cholesterol biosynthesis, ATP yield calculations

Overview of Lipid Metabolism

Fatty acids are the most energy-dense biological fuel molecules, yielding approximately 9 kcal/g compared to ~4 kcal/g for carbohydrates and proteins. This high energy density arises from the highly reduced state of the carbon atoms in fatty acid chains — more C–H bonds means more electrons available for oxidative phosphorylation.

In the body, fatty acids are stored as triacylglycerols (triglycerides) in adipose tissue. A 70 kg adult stores roughly 100,000–130,000 kcal in fat reserves, compared to only ~1,600 kcal in glycogen. This makes fat the dominant energy reserve, capable of sustaining life for weeks during starvation.

Mobilization of Fat Stores

During fasting, exercise, or stress, hormonal signals trigger lipolysis:

Hormone-sensitive lipase (HSL) is activated by glucagon and epinephrine (via cAMP/PKA pathway) and inhibited by insulin. It cleaves triacylglycerols into free fatty acids and glycerol.
Free fatty acids are transported in the blood bound to serum albumin (each albumin molecule can carry up to 10 fatty acids).
Glycerol is transported to the liver, where it enters glycolysis or gluconeogenesis via glycerol-3-phosphate and dihydroxyacetone phosphate (DHAP).

Once fatty acids reach target tissues (muscle, heart, liver), they must cross the mitochondrial membranes to undergo oxidation in the matrix. Short- and medium-chain fatty acids can diffuse freely, but long-chain fatty acids ($\geq$ C14) require the carnitine shuttle system.

The Carnitine Shuttle

Before entering the mitochondrial matrix, long-chain fatty acids must be activated and transported across the inner mitochondrial membrane. This process begins with the formation of acyl-CoA on the outer mitochondrial membrane by acyl-CoA synthetase (thiokinase):

$$\text{Fatty acid} + \text{CoA} + \text{ATP} \rightarrow \text{Acyl-CoA} + \text{AMP} + \text{PP}_i \quad (\text{costs 2 ATP equivalents})$$

The pyrophosphate ($\text{PP}_i$) is immediately hydrolyzed by pyrophosphatase, making the reaction irreversible and effectively consuming 2 ATP equivalents (ATP $\rightarrow$ AMP).

Three Steps of the Shuttle

CPT-I (carnitine palmitoyltransferase I, outer membrane): Transfers the acyl group from CoA to carnitine, forming acylcarnitine. This is the rate-limiting step and the key regulatory point.
Carnitine-acylcarnitine translocase: Carries acylcarnitine across the inner membrane in exchange for free carnitine moving out.
CPT-II (carnitine palmitoyltransferase II, inner membrane, matrix side): Regenerates acyl-CoA from acylcarnitine using mitochondrial CoA. The freed carnitine returns via the translocase.

Regulation: Malonyl-CoA Inhibition

CPT-I is inhibited by malonyl-CoA, the first committed intermediate of fatty acid synthesis. This reciprocal regulation prevents the futile cycle of simultaneously synthesizing and degrading fatty acids. When the cell is in an anabolic state (high insulin, active lipogenesis), malonyl-CoA levels rise, blocking fatty acid entry into mitochondria for oxidation.

$\beta$-Oxidation

$\beta$-Oxidation is a repeating four-step cycle that sequentially removes two-carbon units from the carboxyl end of acyl-CoA, releasing them as acetyl-CoA. The process occurs in the mitochondrial matrix and is named for the oxidation at the $\beta$-carbon (C3) of the acyl chain.

The Four Steps (per cycle)

Oxidation (acyl-CoA dehydrogenase): Introduces a trans-$\Delta^2$ double bond between C2 and C3. FAD is reduced to FADH$_2$.
Hydration (enoyl-CoA hydratase): Adds water across the double bond, forming L-$\beta$-hydroxyacyl-CoA.
Oxidation ($\beta$-hydroxyacyl-CoA dehydrogenase): Oxidizes the hydroxyl group to a ketone ($\beta$-ketoacyl-CoA). NAD$^+$ is reduced to NADH.
Thiolysis ($\beta$-ketothiolase): Cleaves the $\beta$-ketoacyl-CoA with a free CoA molecule, releasing acetyl-CoA and a shortened acyl-CoA (two carbons shorter).

For a saturated fatty acid with $n$ carbon atoms, the total products from complete$\beta$-oxidation are:

$$\left(\frac{n}{2} - 1\right) \text{ cycles} \;\rightarrow\; \frac{n}{2} \text{ acetyl-CoA} \;+\; \left(\frac{n}{2} - 1\right) \text{ FADH}_2 \;+\; \left(\frac{n}{2} - 1\right) \text{ NADH}$$

The final cycle produces two acetyl-CoA molecules directly from the 4-carbon acetoacetyl-CoA intermediate, which is why only $(n/2 - 1)$ cycles are needed rather than $n/2$.

ATP Yield from Fatty Acid Oxidation

Let us calculate the complete ATP yield from the oxidation of palmitate (C16:0), the most abundant saturated fatty acid in the human body.

Palmitate Oxidation Breakdown

$\beta$-Oxidation: 7 cycles $\rightarrow$ 8 acetyl-CoA + 7 FADH$_2$ + 7 NADH
Each acetyl-CoA enters the TCA cycle, yielding 3 NADH + 1 FADH$_2$ + 1 GTP = 10 ATP
Each NADH from $\beta$-oxidation yields 2.5 ATP via oxidative phosphorylation
Each FADH$_2$ from $\beta$-oxidation yields 1.5 ATP via oxidative phosphorylation
Subtract 2 ATP equivalents for initial fatty acid activation (ATP $\rightarrow$ AMP + PP$_i$)

$$\text{Total ATP} = 8(10) + 7(2.5) + 7(1.5) - 2 = 80 + 17.5 + 10.5 - 2 = \boxed{106 \text{ ATP}}$$

Compare this with the ~30–32 ATP generated from complete glucose oxidation. Palmitate (molecular weight 256 g/mol) yields 106 ATP, while glucose (180 g/mol) yields ~30–32 ATP. On a per-gram basis:

$$\text{Palmitate: } \frac{106 \text{ ATP}}{256 \text{ g/mol}} = 0.414 \text{ ATP/g} \qquad \text{Glucose: } \frac{32 \text{ ATP}}{180 \text{ g/mol}} = 0.178 \text{ ATP/g}$$

Fatty acids generate over twice the ATP per gram compared to glucose, explaining the evolutionary advantage of storing energy as fat rather than glycogen.

Unsaturated and Odd-Chain Fatty Acid Oxidation

Most naturally occurring fatty acids are unsaturated (contain one or more double bonds) or, less commonly, have odd-numbered carbon chains. These require additional enzymatic steps beyond the standard$\beta$-oxidation spiral.

Unsaturated Fatty Acids

Monounsaturated (e.g., oleate, C18:1 cis-$\Delta^9$): After three normal $\beta$-oxidation cycles, the cis-$\Delta^3$ double bond is in the wrong configuration. Enoyl-CoA isomerase converts it fromcis-$\Delta^3$ to trans-$\Delta^2$, allowing normal$\beta$-oxidation to continue. This bypasses one FADH$_2$ production step.
Polyunsaturated (e.g., linoleate, C18:2): Requires an additional enzyme,2,4-dienoyl-CoA reductase (NADPH-dependent), to handle conjugated double bond systems that arise during oxidation.

Odd-Chain Fatty Acids

Odd-chain fatty acids (common in ruminant fats and some dairy products) undergo normal$\beta$-oxidation until the final cycle, which produces one propionyl-CoA (3 carbons) instead of acetyl-CoA. Propionyl-CoA is then converted to succinyl-CoA, a TCA cycle intermediate:

$$\text{Propionyl-CoA} \xrightarrow[\text{biotin}]{\text{propionyl-CoA carboxylase}} \text{D-Methylmalonyl-CoA} \xrightarrow{\text{racemase}} \text{L-Methylmalonyl-CoA} \xrightarrow[\text{vitamin B}_{12}]{\text{mutase}} \text{Succinyl-CoA}$$

This pathway requires both biotin and vitamin B$_{12}$ (cobalamin) as cofactors. Deficiency of B$_{12}$ leads to methylmalonic acidemia, a diagnostic marker.

Ketogenesis

During prolonged fasting, starvation, or uncontrolled diabetes, the liver produces large quantities of acetyl-CoA from $\beta$-oxidation that exceed the capacity of the TCA cycle (due to depletion of oxaloacetate, which is diverted to gluconeogenesis). The excess acetyl-CoA is channeled into the synthesis of ketone bodies in the liver mitochondria.

$$2\,\text{Acetyl-CoA} \xrightarrow{\text{thiolase}} \text{Acetoacetyl-CoA} \xrightarrow{\text{HMG-CoA synthase}} \text{HMG-CoA} \xrightarrow{\text{HMG-CoA lyase}} \text{Acetoacetate} + \text{Acetyl-CoA}$$

Acetoacetate can then be reduced to $\beta$-hydroxybutyrate (by $\beta$-hydroxybutyrate dehydrogenase, using NADH) or spontaneously decarboxylated to acetone(which is exhaled — producing the characteristic fruity breath odor in ketoacidosis).

Ketone Bodies as Fuel

Ketone bodies are water-soluble and do not require albumin transport or the carnitine shuttle.
The brain, which normally relies on glucose, can adapt to use ketone bodies for up to 75% of its energy needs during prolonged fasting.
Heart muscle and renal cortex preferentially oxidize ketone bodies even in the fed state.
The liver cannot use ketone bodies (lacks succinyl-CoA:acetoacetate CoA transferase, also called thiophorase).

Diabetic Ketoacidosis (DKA)

In uncontrolled type 1 diabetes, the absence of insulin leads to unopposed lipolysis and massive$\beta$-oxidation. The resulting flood of acetyl-CoA overwhelms the TCA cycle, driving uncontrolled ketogenesis. Acetoacetate and $\beta$-hydroxybutyrate are acids ($\text{p}K_a \approx 3.6-4.7$), and their accumulation causes life-threatening metabolic acidosis with blood pH dropping below 7.3.

Fatty Acid Synthesis (Lipogenesis)

Fatty acid synthesis occurs in the cytoplasm (not in mitochondria like $\beta$-oxidation) and is essentially the reverse process, though it uses different enzymes, different electron carriers, and a different acyl group carrier. The spatial separation of synthesis and degradation allows independent regulation of these opposing pathways.

The Committed Step: Acetyl-CoA Carboxylase (ACC)

The rate-limiting step is catalyzed by acetyl-CoA carboxylase, a biotin-dependent enzyme that carboxylates acetyl-CoA to malonyl-CoA:

$$\text{Acetyl-CoA} + \text{CO}_2 + \text{ATP} \xrightarrow[\text{biotin}]{\text{ACC}} \text{Malonyl-CoA} + \text{ADP} + \text{P}_i$$

ACC is activated by citrate and insulin signaling, and inhibited by palmitoyl-CoA (feedback) and AMPK-mediated phosphorylation (energy-depleted state).

Fatty acid synthase (FAS) is a large, multi-functional enzyme complex that carries out a repeating cycle of four reactions: condensation, reduction (NADPH), dehydration, and reduction (NADPH). Each cycle adds 2 carbons from malonyl-CoA to the growing chain. The primary product is palmitate (C16:0).

$$8\,\text{Acetyl-CoA} + 14\,\text{NADPH} + 7\,\text{ATP} \rightarrow \text{Palmitate} + 8\,\text{CoA} + 14\,\text{NADP}^+ + 7\,\text{ADP} + 7\,\text{P}_i + 6\,\text{H}_2\text{O}$$

The NADPH required for lipogenesis comes from two sources: the pentose phosphate pathway (oxidative branch, via glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase) and the malic enzyme reaction (malate $\rightarrow$ pyruvate + CO$_2$ + NADPH) in the citrate shuttle system.

Cholesterol Synthesis

Cholesterol is an essential membrane component and the precursor to steroid hormones, bile acids, and vitamin D. All 27 carbons of cholesterol are derived from acetyl-CoA in a complex, multi-step pathway that occurs primarily in the liver and intestinal mucosa.

Key Stages of Cholesterol Biosynthesis

Acetyl-CoA $\rightarrow$ Mevalonate: Three acetyl-CoA molecules condense to form HMG-CoA, which is then reduced to mevalonate by HMG-CoA reductase (the rate-limiting enzyme and the target of statins).
Mevalonate $\rightarrow$ Isopentenyl-PP: Mevalonate is phosphorylated and decarboxylated to form the 5-carbon isoprene unit, isopentenyl pyrophosphate.
Isopentenyl-PP $\rightarrow$ Squalene: Six isoprene units (C5) condense to form the 30-carbon linear molecule squalene.
Squalene $\rightarrow$ Lanosterol $\rightarrow$ Cholesterol: Squalene undergoes cyclization to form lanosterol, which is then converted to cholesterol through ~19 additional enzymatic steps.

Regulation of Cholesterol Synthesis

SREBP (sterol regulatory element-binding protein): A transcription factor that activates genes encoding HMG-CoA reductase and the LDL receptor when intracellular cholesterol is low.
Feedback inhibition: Cholesterol itself promotes degradation of HMG-CoA reductase (via the Insig/SCAP/SREBP pathway) and suppresses its transcription.
Statins (atorvastatin, rosuvastatin, etc.) are competitive inhibitors of HMG-CoA reductase, representing one of the most widely prescribed drug classes worldwide for lowering LDL cholesterol and reducing cardiovascular risk.

Python: $\beta$-Oxidation ATP Yield Calculator

Use the interactive Python code runner below to calculate the ATP yield from complete $\beta$-oxidation of any even-chain saturated fatty acid. The program computes the number of oxidation cycles, reduced coenzymes produced, and total ATP generated. It also plots a comparison chart for fatty acids of different chain lengths (C12 through C20).

Beta-Oxidation ATP Yield Calculator

Python

Calculate and visualize ATP production from fatty acid oxidation

beta_oxidation_calculator.py137 lines

import numpy as np
import matplotlib.pyplot as plt

def beta_oxidation_atp(chain_length):
    """
    Calculate ATP yield from complete beta-oxidation of a saturated fatty acid.

Parameters:
        chain_length (int): Number of carbons in the fatty acid (must be even)

Returns:
        dict with detailed breakdown of ATP production
    """
    if chain_length < 4 or chain_length % 2 != 0:
        raise ValueError("Chain length must be an even number >= 4")

cycles = chain_length // 2 - 1
    acetyl_coa = chain_length // 2
    fadh2 = cycles
    nadh_beta = cycles

# Each acetyl-CoA yields 10 ATP via TCA cycle + oxidative phosphorylation
    # (3 NADH x 2.5 + 1 FADH2 x 1.5 + 1 GTP = 10)
    atp_from_acetyl = acetyl_coa * 10
    atp_from_nadh = nadh_beta * 2.5
    atp_from_fadh2 = fadh2 * 1.5
    activation_cost = 2  # ATP -> AMP + PPi equivalent

total_atp = atp_from_acetyl + atp_from_nadh + atp_from_fadh2 - activation_cost

return {
        'chain_length': chain_length,
        'cycles': cycles,
        'acetyl_coa': acetyl_coa,
        'nadh': nadh_beta,
        'fadh2': fadh2,
        'atp_from_acetyl': atp_from_acetyl,
        'atp_from_nadh': atp_from_nadh,
        'atp_from_fadh2': atp_from_fadh2,
        'activation_cost': activation_cost,
        'total_atp': total_atp
    }

# --- Calculate for palmitate (C16) as the primary example ---
print("=" * 60)
print("  BETA-OXIDATION ATP YIELD CALCULATOR")
print("=" * 60)

result = beta_oxidation_atp(16)
print(f"\nFatty Acid: Palmitate (C{result['chain_length']}:0)")
print(f"{'='*45}")
print(f"  Beta-oxidation cycles:      {result['cycles']}")
print(f"  Acetyl-CoA produced:        {result['acetyl_coa']}")
print(f"  NADH produced (beta-ox):    {result['nadh']}")
print(f"  FADH2 produced (beta-ox):   {result['fadh2']}")
print(f"{'='*45}")
print(f"  ATP from acetyl-CoA (TCA):  {result['atp_from_acetyl']:.1f}")
print(f"  ATP from NADH (x 2.5):      {result['atp_from_nadh']:.1f}")
print(f"  ATP from FADH2 (x 1.5):     {result['atp_from_fadh2']:.1f}")
print(f"  Activation cost:            -{result['activation_cost']}")
print(f"{'='*45}")
print(f"  TOTAL ATP YIELD:            {result['total_atp']:.1f} ATP")
print()

# --- Compare multiple chain lengths ---
chain_lengths = [12, 14, 16, 18, 20]
labels = ['Laurate\n(C12)', 'Myristate\n(C14)', 'Palmitate\n(C16)', 'Stearate\n(C18)', 'Arachidate\n(C20)']
atp_values = []
atp_per_carbon = []

print("\nComparison of ATP Yield by Chain Length:")
print(f"{'Chain':<10} {'Cycles':<8} {'AcCoA':<8} {'NADH':<8} {'FADH2':<8} {'Total ATP':<10} {'ATP/C':<8}")
print("-" * 60)

for cl in chain_lengths:
    r = beta_oxidation_atp(cl)
    atp_values.append(r['total_atp'])
    atp_per_carbon.append(r['total_atp'] / cl)
    print(f"C{cl:<9} {r['cycles']:<8} {r['acetyl_coa']:<8} {r['nadh']:<8} {r['fadh2']:<8} {r['total_atp']:<10.1f} {r['total_atp']/cl:<8.2f}")

# --- Generate comparison bar chart ---
fig, (ax1, ax2) = plt.subplots(1, 2, figsize=(14, 6))
fig.patch.set_facecolor('#0a0a0a')

# Plot 1: Total ATP yield
colors = ['#34d399', '#6ee7b7', '#10b981', '#059669', '#047857']
bars1 = ax1.bar(labels, atp_values, color=colors, edgecolor='#065f46', linewidth=1.2, width=0.6)

ax1.set_facecolor('#0a0a0a')
ax1.set_title('Total ATP Yield from Beta-Oxidation', color='#6ee7b7', fontsize=14, fontweight='bold', pad=12)
ax1.set_ylabel('ATP Molecules', color='#a7f3d0', fontsize=12)
ax1.set_xlabel('Fatty Acid', color='#a7f3d0', fontsize=12)
ax1.tick_params(colors='#9ca3af')
ax1.spines['bottom'].set_color('#065f46')
ax1.spines['left'].set_color('#065f46')
ax1.spines['top'].set_visible(False)
ax1.spines['right'].set_visible(False)
ax1.set_axisbelow(True)
ax1.yaxis.grid(True, color='#1a3a2a', linestyle='--', alpha=0.5)

for bar, val in zip(bars1, atp_values):
    ax1.text(bar.get_x() + bar.get_width()/2., bar.get_height() + 1,
             f'{val:.0f}', ha='center', va='bottom', color='#6ee7b7', fontweight='bold', fontsize=11)

# Plot 2: ATP per carbon atom (efficiency)
bars2 = ax2.bar(labels, atp_per_carbon, color=['#f59e0b', '#fbbf24', '#f59e0b', '#d97706', '#b45309'],
                edgecolor='#78350f', linewidth=1.2, width=0.6)

ax2.set_facecolor('#0a0a0a')
ax2.set_title('Energy Efficiency (ATP per Carbon)', color='#fde68a', fontsize=14, fontweight='bold', pad=12)
ax2.set_ylabel('ATP / Carbon Atom', color='#fde68a', fontsize=12)
ax2.set_xlabel('Fatty Acid', color='#fde68a', fontsize=12)
ax2.tick_params(colors='#9ca3af')
ax2.spines['bottom'].set_color('#78350f')
ax2.spines['left'].set_color('#78350f')
ax2.spines['top'].set_visible(False)
ax2.spines['right'].set_visible(False)
ax2.set_axisbelow(True)
ax2.yaxis.grid(True, color='#3a2a1a', linestyle='--', alpha=0.5)

for bar, val in zip(bars2, atp_per_carbon):
    ax2.text(bar.get_x() + bar.get_width()/2., bar.get_height() + 0.02,
             f'{val:.2f}', ha='center', va='bottom', color='#fde68a', fontweight='bold', fontsize=11)

plt.tight_layout(pad=3.0)
plt.savefig('plot.png', dpi=150, bbox_inches='tight', facecolor='#0a0a0a', edgecolor='none')
plt.show()

# Compare with glucose
print(f"\n{'='*60}")
print("  COMPARISON WITH GLUCOSE OXIDATION")
print(f"{'='*60}")
print(f"  Glucose (C6H12O6):    ~30-32 ATP  |  ~5.3 ATP/carbon")
print(f"  Palmitate (C16H32O2): ~106 ATP    |  ~6.63 ATP/carbon")
print(f"\n  Fatty acids yield ~25% more ATP per carbon than glucose!")
print(f"  This explains why fats store ~9 kcal/g vs ~4 kcal/g for carbs.")

Click Run to execute the Python code

Code will be executed with Python 3 on the server

Key Concepts

1. Fatty acids are the body's most energy-dense fuel (~9 kcal/g), stored as triacylglycerols in adipose tissue and mobilized by hormone-sensitive lipase in response to glucagon and epinephrine.

2. The carnitine shuttle (CPT-I, translocase, CPT-II) transports long-chain acyl groups into the mitochondrial matrix. CPT-I is inhibited by malonyl-CoA, preventing simultaneous synthesis and oxidation.

3. $\beta$-Oxidation is a four-step spiral (oxidation, hydration, oxidation, thiolysis) that removes 2-carbon units as acetyl-CoA, producing FADH$_2$ and NADH with each cycle.

4. Complete oxidation of palmitate (C16:0) yields 106 ATP (after subtracting 2 ATP for activation), compared to ~30–32 ATP from glucose.

5. Unsaturated fatty acids require isomerase and reductase enzymes for $\beta$-oxidation. Odd-chain fatty acids produce propionyl-CoA, converted to succinyl-CoA via a vitamin B$_{12}$-dependent pathway.

6. Ketogenesis in the liver converts excess acetyl-CoA to ketone bodies (acetoacetate, $\beta$-hydroxybutyrate, acetone) during fasting. The brain can adapt to use ketone bodies as its primary fuel source.

7. Fatty acid synthesis occurs in the cytoplasm using acetyl-CoA carboxylase (rate-limiting, biotin-dependent) and fatty acid synthase. It requires NADPH and produces palmitate as the primary product.

8. Cholesterol synthesis proceeds through the mevalonate pathway with HMG-CoA reductase as the rate-limiting enzyme and the pharmacological target of statins. Regulation involves SREBP-mediated transcriptional control and feedback inhibition.

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