Biochemistry: Lipid Metabolism

Lipid metabolism is the set of biochemical pathways that build, store, mobilize, and break down fats. Because lipids are both a major energy reserve and structural components of membranes, their metabolism sits at the center of human physiology. When these pathways drift out of balance, the consequences show up in common disorders such as obesity, type 2 diabetes, and cardiovascular disease.

At a practical level, lipid metabolism answers four recurring questions in the body: When should energy be stored as fat? When should fat be released for fuel? What happens when carbohydrate is scarce? How are cholesterol and other lipids managed to support membranes and hormones without damaging blood vessels?

Why lipid metabolism matters

Triglycerides stored in adipose tissue are the body’s most concentrated energy bank. Gram for gram, fatty acids yield more energy than carbohydrates because they are more reduced. That efficiency becomes critical during fasting, endurance exercise, and illness.

However, the same storage advantage becomes a liability when energy intake chronically exceeds expenditure. Persistently elevated circulating fatty acids and triglyceride-rich lipoproteins contribute to insulin resistance, fatty liver, and atherogenic dyslipidemia, key links between lipid metabolism and cardiometabolic disease.

Fatty acid synthesis: storing energy when fuel is abundant

Fatty acid synthesis is most active in the fed state, particularly in liver and adipose tissue, when glucose and insulin are high. The pathway converts excess carbon (often from carbohydrate) into fatty acids, which are then esterified into triglycerides for storage or packaged for transport.

Substrates and logic of synthesis

Cells cannot directly turn acetyl-CoA into glucose, but they can turn acetyl-CoA into fatty acids. When glycolysis and the citric acid cycle are well supplied, citrate accumulates and can be exported from mitochondria into the cytosol. There, citrate is cleaved back to acetyl-CoA to feed lipogenesis.

The committed step is the formation of malonyl-CoA, which supplies two-carbon units for chain elongation. The growing fatty acid chain is built iteratively until a typical product like palmitate (16 carbons) is formed. This process requires reducing power, largely in the form of NADPH, tying lipid synthesis to pathways that generate NADPH in the cytosol.

Coordinated regulation with fat burning

A central regulatory theme is that the body avoids synthesizing and breaking down fatty acids at the same time. Malonyl-CoA not only supports synthesis; it also inhibits the mitochondrial entry of fatty acids for oxidation by restraining the carnitine-dependent transport step. In the fed state, this prevents a futile cycle and favors storage.

In insulin resistance, this coordination becomes distorted. The liver may continue producing triglycerides even when peripheral tissues are overloaded, contributing to elevated VLDL, fatty liver, and the lipid abnormalities frequently seen in type 2 diabetes.

β-oxidation: mobilizing fatty acids for energy

β-oxidation is the major pathway for fatty acid degradation. It occurs primarily in mitochondria and is most important during fasting, prolonged exercise, or any state where insulin is low and counter-regulatory hormones favor fuel mobilization.

From adipose to mitochondria

In the fasting state, triglycerides in adipose tissue are hydrolyzed to release free fatty acids into the bloodstream. These fatty acids travel bound to albumin and are taken up by tissues such as liver and muscle.

Long-chain fatty acids must be transported into mitochondria before they can be oxidized. Once inside, β-oxidation repeatedly removes two-carbon fragments as acetyl-CoA while generating electron carriers that drive ATP production through oxidative phosphorylation.

What β-oxidation produces and why it matters

The acetyl-CoA generated has two major fates:

• In muscle and many tissues, acetyl-CoA enters the citric acid cycle for immediate energy.
• In liver during fasting, acetyl-CoA can be diverted toward ketone body production when carbohydrate availability is low.

When β-oxidation is impaired or overwhelmed, fatty acids can accumulate in tissues, contributing to lipotoxicity and metabolic stress. In obesity, elevated fatty acid flux from adipose tissue is one mechanism that worsens insulin resistance in liver and muscle.

Ketogenesis: a fasting adaptation with clinical relevance

Ketogenesis is the hepatic production of ketone bodies from acetyl-CoA. It becomes significant when glucose supply is limited and fatty acid oxidation is high, such as during prolonged fasting, carbohydrate restriction, or uncontrolled diabetes.

Why the liver makes ketones

The liver cannot export acetyl-CoA directly. During fasting, oxaloacetate is often pulled toward gluconeogenesis to maintain blood glucose. With less oxaloacetate available, the citric acid cycle slows, and acetyl-CoA accumulates. Converting acetyl-CoA into ketone bodies provides a soluble fuel that can be shipped to other organs.

Ketone bodies are used by many tissues, including the brain after adaptation to fasting, reducing the need for glucose and sparing muscle protein from being broken down for gluconeogenesis.

Ketosis versus ketoacidosis

Physiologic ketosis is a regulated response with ketone levels that rise but remain compatible with normal blood pH. In contrast, diabetic ketoacidosis results from severe insulin deficiency. Unrestrained lipolysis and ketogenesis produce ketones faster than they can be utilized, driving metabolic acidosis. This distinction matters clinically because the same pathway underlies both states, but the hormonal control is profoundly different.

Cholesterol metabolism: essential molecule, dangerous excess

Cholesterol is indispensable for cell membranes, bile acids, and steroid hormone synthesis. Yet it is not used for energy, so its metabolism is about synthesis, transport, and disposal.

Synthesis and cellular needs

Cells can synthesize cholesterol from acetyl-CoA, especially in the liver. This ensures supply for membrane integrity and hormone production even when dietary intake is low. Because cholesterol is hydrophobic, it travels in blood packaged within lipoproteins.

Lipoprotein transport and cardiovascular disease

Lipoproteins distribute triglycerides and cholesterol among tissues. The clinical importance lies in how cholesterol is delivered to, and removed from, the arterial wall.

• LDL particles are a major carrier of cholesterol to peripheral tissues. Elevated LDL cholesterol is strongly associated with atherosclerotic cardiovascular disease.
• HDL participates in reverse cholesterol transport, helping move cholesterol from tissues back to the liver for processing.

Disruption in lipid handling, common in obesity and type 2 diabetes, often produces a pattern of elevated triglycerides, low HDL, and small dense LDL particles. This combination is particularly atherogenic and helps explain why metabolic disease and cardiovascular risk so often travel together.

Disposal: the exit route matters

Humans cannot degrade the sterol nucleus of cholesterol into CO₂ and water. A major disposal route is conversion to bile acids and secretion into bile. This creates a true excretory pathway, linking hepatic cholesterol management to gastrointestinal handling and overall cholesterol balance.

How lipid metabolism connects to diabetes, obesity, and cardiovascular disease

These conditions intersect through shared biochemical pressures:

• Chronic energy surplus promotes fatty acid synthesis and triglyceride storage.
• Enlarged adipose tissue increases fatty acid release into circulation, especially when insulin action is impaired.
• Elevated hepatic fatty acid influx supports increased VLDL production, raising triglycerides and worsening lipid profiles.
• Excess circulating lipids and ectopic fat in liver and muscle interfere with insulin signaling, reinforcing hyperglycemia and further dysregulation.

In short, lipid metabolism is not a standalone chapter of biochemistry. It is a dynamic system that integrates nutritional state, hormone signaling, and tissue-specific demands. Understanding fatty acid synthesis and β-oxidation, ketogenesis, and cholesterol metabolism provides a coherent framework for why modern cardiometabolic diseases develop and why they are so tightly linked.