When we think about fats, our minds often drift to dietary sources like butter or oil. However, the body has its own sophisticated system for producing fats, known as endogenous fats—primarily in the form of triglycerides. These fats are synthesized internally from excess calories, whether they come from carbohydrates, fats, or proteins, and serve as an essential energy reserve for survival and function.
Endogenous triglycerides are primarily synthesized in the liver, where surplus energy is converted into fat molecules and packaged into very low-density lipoproteins (VLDL) for transport to various tissues. They play a pivotal role in fat storage, contributing to overall energy homeostasis and, in excess, leading to fat accumulation and metabolic disorders like insulin resistance.
But triglycerides don’t just exist in isolation—they are intricately linked to lipoproteins like LDL and HDL, which act as carriers to transport them throughout the body. Interestingly, triglycerides also hold the key to understanding cardiovascular health, with research showing that triglyceride levels often correlate with the presence of small, dense LDL particles—a risk factor for heart disease.
This blog explores the journey of endogenous triglycerides, delving into how and where they are synthesized, their role in energy storage and fat accumulation, and why triglycerides are more informative than LDL when it comes to assessing metabolic health. By unraveling their complex story, we can better understand their crucial role in the body's metabolic framework.
Endogenous Fats: The Body's Internal Fat Production System
While dietary fats (exogenous fats) are absorbed from the food we eat, our body is also capable of synthesizing its own fats, referred to as endogenous fats. This process is critical for maintaining energy balance, cell structure, and metabolic functions, particularly during periods of fasting or insufficient dietary fat intake.
Image Credit: ResearchGate
Endogenous triglycerides (TG) are synthesized by the liver, primarily from excess dietary carbohydrates, and to a lesser extent from proteins and fats. Here’s a step-by-step explanation of how triglycerides are made:
Source of Building Blocks
Carbohydrates: Excess glucose from the diet is the primary source. When glycogen stores are full, the surplus glucose undergoes conversion into triglycerides.
Proteins: Amino acids from protein metabolism can be converted into precursors like acetyl-CoA, which enters the triglyceride synthesis pathway.
Fats: Dietary fats are broken down and transported to the liver, where they can also contribute to triglyceride synthesis.
Conversion of Glucose to Fat (De Novo Lipogenesis)
Glycolysis: Glucose is broken down into pyruvate through glycolysis.
Pyruvate to Acetyl-CoA: Pyruvate enters the mitochondria and is converted to acetyl-CoA.
Citrate Formation and Export: In the citric acid cycle, excess acetyl-CoA is converted to citrate, which is exported from the mitochondria to the cytoplasm when energy demands are low.
Acetyl-CoA to Fatty Acids:
Citrate Lyase converts citrate back into acetyl-CoA in the cytoplasm.
Acetyl-CoA Carboxylase (ACC) converts acetyl-CoA to malonyl-CoA, the first committed step in fatty acid synthesis.
Fatty Acid Synthase (FAS) catalyzes the formation of palmitic acid (a 16-carbon fatty acid) from acetyl-CoA and malonyl-CoA, using NADPH as an energy source.
Elongation and Desaturation: Palmitic acid can be further elongated and desaturated to form other fatty acids like oleic acid.
Formation of Triglycerides
Activation of Fatty Acids: Fatty acids are activated to form fatty acyl-CoA.
Glycerol Backbone: The liver generates glycerol-3-phosphate (the backbone of triglycerides) through glycolysis or from free glycerol.
Assembly: Three fatty acyl-CoA molecules attach to one glycerol-3-phosphate molecule in a stepwise manner via the enzymes acyltransferases, forming a triglyceride.
Packaging and Transport
Once synthesized, triglycerides are packaged into very low-density lipoproteins (VLDL) in the liver.
VLDLs are secreted into the bloodstream and deliver triglycerides to tissues like adipose tissue (for storage) or muscles (for energy).
Key Influences on Triglyceride Synthesis
Excess Carbohydrates: High intake of refined carbs increases triglyceride production.
Insulin: Stimulates de novo lipogenesis by upregulating enzymes like acetyl-CoA carboxylase and fatty acid synthase.
Alcohol: Promotes fatty acid synthesis and triglyceride accumulation in the liver.
Hormones: Glucagon and stress hormones (e.g., cortisol) reduce triglyceride synthesis by opposing insulin action.
By this process, endogenous triglycerides serve as a form of long-term energy storage and are used to transport fatty acids throughout the body for various cellular functions.
The Liver's Role in Endogenous Fat Production
The liver is the central hub for the production, modification, and distribution of endogenous fats.
Synthesis: Fatty acids are synthesized in the liver from acetyl-CoA. These are assembled into triglycerides, the main form of stored fat.
Packaging into VLDL: Triglycerides produced in the liver are packaged into very-low-density lipoproteins (VLDL). VLDL particles are responsible for transporting triglycerides and cholesterol from the liver to peripheral tissues.
Release into Circulation: VLDL is released into the bloodstream, where it travels to deliver triglycerides to muscles (for energy) and adipose tissue (for storage).
Image Credit: Frontiers
Where Do Fats Go from the Liver?
Once packaged into VLDL, fats follow a complex path:
Peripheral Tissues: Lipoprotein lipase (LPL) in the capillaries of muscles and adipose tissue breaks down the triglycerides in VLDL into free fatty acids. These are taken up by tissues:
Muscles: Free fatty acids are oxidized to produce ATP.
Adipose Tissue: Free fatty acids are re-esterified into triglycerides for long-term storage.
Transformation into LDL: After delivering triglycerides, VLDL is converted into intermediate-density lipoproteins (IDL) and eventually into low-density lipoproteins (LDL). LDL serves as a cholesterol carrier, delivering cholesterol to cells for membrane synthesis, hormone production, and other functions.
Recycling via HDL: High-density lipoproteins (HDL) collect excess cholesterol from tissues and transport it back to the liver in a process called reverse cholesterol transport, ensuring balance and preventing cholesterol accumulation.
The Connection Between LDL and Triglycerides
Understanding the relationship between LDL cholesterol and triglycerides provides valuable insights into cardiovascular risk. Triglycerides, serve as an energy reserve. However, when triglyceride levels are elevated, they indicate a potential risk for heart attacks that is often more predictive than LDL cholesterol levels.
The Role of Fasting Triglycerides
The reliability of triglyceride measurements hinges on fasting conditions. Many individuals, when having their lipid panels checked, fail to fast adequately, leading to erratic triglyceride readings. True fasting triglycerides, however, can be highly indicative of cardiovascular health. Research shows that:
High triglycerides correlate with heart attack risk: A hazard risk ratio of 1.8 means that elevated triglycerides increase the risk of a heart attack by 80%.
This risk ratio is significantly more predictive than LDL cholesterol, which has a hazard ratio of 1.3 (30% increased risk).
Despite their importance, triglycerides are often overlooked in clinical settings. This neglect stems from historical factors:
Fasting Inconsistencies: Non-fasting triglyceride levels vary widely, leading to less reliable results.
Lack of Treatment Options: Until recently, no effective medications were available to lower triglycerides. Even now, existing treatments come with potential side effects, making physicians hesitant to prescribe them.
Lack of Understanding: Lack of clear understanding about the source of triglycerides, which is excess carbohydrate consumption. This led to over focus on fat consumption and cholesterol as opposed to restricting carb intake.
The Interplay Between LDL and Triglycerides
The connection between LDL and triglycerides lies in their shared metabolic pathways:
Elevated triglycerides often indicate the presence of small, dense LDL particles. Unlike large, buoyant LDL particles, small, dense LDL is more atherogenic, meaning it contributes more readily to plaque formation in arteries.
A high triglyceride level coupled with low HDL cholesterol and small, dense LDL particles paints a clear picture of heightened cardiovascular risk.
Clinical Implications
To assess cardiovascular risk accurately, it’s essential to evaluate both LDL cholesterol and triglycerides together. This holistic approach offers a more nuanced understanding of lipid health and helps identify individuals at greater risk of heart disease.
As researchers and clinicians continue to explore the lipid landscape, the focus is gradually shifting toward addressing triglycerides as a significant marker of cardiovascular risk. Proper fasting protocols and improved awareness of triglyceride management are critical steps in bridging the gap between clinical practice and patient outcomes.
Understanding LDL: Large Buoyant vs. Small Dense and Their Relationship to Triglycerides
LDL particles, often labeled as "bad cholesterol," are not uniform. They exist in two primary forms, each with distinct properties and implications for cardiovascular health:
Large Buoyant LDL:
Properties:
Comprises ~80% of total LDL.
Cardiovascularly neutral – neither harmful nor beneficial.
Large in size and floats easily through the bloodstream without adhering to arterial walls.
Lacks the capacity to penetrate endothelial cells and initiate plaque formation.
Role:
Functions as a harmless transporter of cholesterol.
Moves through the arteries like balloons in a wind tunnel, without causing damage.
Small Dense LDL:
Properties:
Comprises ~20% of total LDL.
Small in size, capable of penetrating endothelial cells to initiate plaque formation.
Dense and sinks, increasing the likelihood of lodging in arterial nooks and crannies.
Has an inflammatory surface, further contributing to cardiovascular risk.
Role:
Directly associated with atherogenesis (plaque formation).
The main contributor to cardiovascular disease risk.
Image Credit: Absolute Health
What Determines LDL Type?
The type of LDL particles present in your blood is heavily influenced by triglyceride levels.
High Triglycerides:
Associated with small, dense LDL.
Indicates the liver's production of VLDL in response to excess carb consumption.
These VLDL particles, after offloading triglycerides, evolve into small, dense LDL.
Low Triglycerides:
Associated with large, buoyant LDL.
Suggests minimal carb consumption and efficient lipid metabolism.
Key Insight:
Fasting triglyceride levels directly reflect how your liver processes dietary carbohydrates, especially sugar.
Chylomicrons and Their Role
Source:
Produced in the intestines in response to dietary fat.
They are massive particles compared to VLDL and are efficiently cleared by the liver.
Relevance:
In a fasting state, triglycerides reflect VLDL, not chylomicrons.
High triglycerides in fasting conditions are a clear marker of excess sugar intake.
Practical Implications
To reduce small, dense LDL:
Lower sugar consumption to minimize VLDL production.
Reduce frequent insulin spikes, which promotes fat production, via VLDL.
Focus on dietary and lifestyle changes that lower fasting triglycerides.
Why Understanding This Matters
Most standard lipid panels only provide a snapshot of total LDL levels without distinguishing between large, buoyant and small, dense LDL. This lack of nuance can lead to misguided treatment recommendations, such as prescribing statins without addressing the root cause (e.g., sugar consumption).
Takeaway Message
Endogenous triglycerides are much more than just molecules of stored energy; they are central players in the body's metabolic and cardiovascular health. Synthesized in the liver from excess calories—whether from carbohydrates, fats, or proteins—they are transported via lipoproteins like VLDL to tissues for storage or use. While essential for survival, elevated triglycerides can become a double-edged sword, contributing to fat accumulation, insulin resistance, and the formation of small, dense LDL particles—key drivers of cardiovascular risk.
We’ve uncovered how triglycerides bridge the gap between energy metabolism and lipoprotein dynamics, highlighting their crucial role in the body’s metabolic balance. More importantly, we’ve learned why focusing on triglyceride levels, rather than just cholesterol or LDL alone, provides a more complete picture of metabolic health.
As we continue this exploration into the intricate world of fats and lipoproteins, the next step is to examine lipid panels, the diagnostic tool that helps us decode cholesterol, triglycerides, and their carriers. By understanding the interplay between these components, we can better assess and manage overall metabolic and cardiovascular health. Stay tuned as we dive deeper into this crucial topic and learn how to interpret what your lipid panel is really telling you.
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