De novo lipogenesis (DNL) is a metabolic process where the body converts excess energy from non-fat sources, primarily carbohydrates, into long-term stored body fat. As modern diets have become richer in refined sugars and processed foods, the rate of DNL has accelerated in many individuals. Understanding DNL is important because its dysregulation is closely linked to several common metabolic disorders. The process acts as a metabolic overflow valve, packaging fuel that cannot be immediately used or stored as glycogen for future use.
Defining De Novo Lipogenesis
De novo lipogenesis (DNL) translates to “new creation of fat,” describing the synthesis of fatty acids from simpler, non-lipid molecules. This process creates the body’s own fat rather than storing fat consumed through the diet. The main inputs for DNL are excess dietary carbohydrates, though amino acids from protein can also serve as precursors.
The newly synthesized fatty acids combine with glycerol to form triglycerides, the molecules used for long-term energy storage in adipose tissue and the liver. While DNL occurs in several tissues, the primary sites in humans are the liver (in hepatocytes) and, to a lesser extent, adipose tissue. The liver is highly responsive to the signaling that initiates DNL, acting as the central processing unit for nutrient fate.
DNL is generally a minor source of body fat in healthy individuals consuming a balanced diet. It only becomes a significant contributor to fat storage when caloric intake substantially exceeds energy expenditure and the body’s short-term carbohydrate stores, like glycogen, are saturated. The process is tightly regulated by hormones like insulin, which signals an energy surplus and initiates the storage protocol.
The Metabolic Steps
The DNL pathway begins with the breakdown of excess carbohydrates, such as glucose, into the two-carbon molecule acetyl-CoA. This conversion occurs within the mitochondria, where fuel is usually oxidized for immediate energy. Since fatty acid synthesis takes place outside the mitochondria in the cytosol, acetyl-CoA must first be transported.
Transport is accomplished by the citrate shuttle, combining acetyl-CoA with oxaloacetate to form citrate, which crosses the mitochondrial membrane. In the cytosol, citrate is cleaved back into acetyl-CoA, the fundamental building block for fat. The next step involves the enzyme acetyl-CoA carboxylase, which converts two-carbon acetyl-CoA into three-carbon malonyl-CoA. This step is considered the commitment switch for long-term storage and is a point of metabolic regulation.
Finally, a multi-enzyme complex called fatty acid synthase uses malonyl-CoA units to repeatedly add two-carbon segments, polymerizing the chain to create a saturated fatty acid. The most common end product is the 16-carbon fatty acid palmitate. These fatty acids are quickly combined with glycerol to form triglycerides, ready for storage or transport.
Dietary Factors Driving the Process
The rate of DNL is highly responsive to diet composition, particularly the quantity and type of carbohydrate consumed. A chronic caloric surplus is the fundamental driver, signaling that energy reserves are high and storage should be prioritized. The specific type of carbohydrate plays a powerful role in determining the speed and extent of the DNL pathway.
Refined sugars and high-glycemic carbohydrates are potent stimulators because they lead to a rapid increase in blood glucose and subsequent high insulin release. Insulin activates transcription factors, such as SREBP-1c, which induce the expression of nearly all DNL enzymes. This hormonal signal effectively turns up the fat-creation machinery in the liver.
Fructose, a simple sugar found in sweeteners like high-fructose corn syrup and sucrose, is a strong inducer of DNL. Unlike glucose, fructose is metabolized almost entirely by the liver and enters the lipogenic pathway, bypassing a major regulatory step. This unregulated entry means fructose quickly and directly provides the necessary intermediates for acetyl-CoA production, accelerating fat synthesis. Fructose is considered a more potent substrate for hepatic lipogenesis than glucose, contributing significantly to the metabolic shift toward fat storage.
Health Consequences and Liver Impact
When DNL is chronically elevated due to persistent overconsumption of energy, consequences center on the liver and systemic metabolic health. The most direct consequence is the development of Non-Alcoholic Fatty Liver Disease (NAFLD)—a buildup of fat in the liver not caused by alcohol. Fatty acids synthesized through DNL are packaged into triglycerides and stored within liver cells, leading to hepatic steatosis. In individuals with NAFLD, DNL accounts for a significant portion of the fat accumulating in the liver.
The accumulation of fat in the liver can progress to Non-Alcoholic Steatohepatitis (NASH), a more severe inflammatory disease involving liver inflammation and damage. Beyond the liver, elevated DNL contributes to dyslipidemia (abnormal lipid levels in the blood). The liver packages newly synthesized triglycerides into very low-density lipoprotein (VLDL) particles, which are secreted into the bloodstream. Increased VLDL secretion raises plasma triglyceride levels and is associated with cardiovascular issues.
Products of excessive DNL, such as toxic lipid metabolites, are implicated in the development of insulin resistance. This resistance means cells respond poorly to insulin, creating a positive feedback loop where the body releases more insulin, further stimulating DNL and worsening metabolic syndrome. This cycle links high rates of DNL to metabolic disorders, including type 2 diabetes and obesity.
Lifestyle Strategies to Reduce DNL
Modulating the rate of DNL is a strategy for improving metabolic health, particularly for individuals with liver fat accumulation. The most effective dietary adjustment involves reducing the caloric load, removing the energy surplus that triggers DNL. Targeting the substrate for the process is also beneficial, requiring a reduction in the intake of refined carbohydrates and free sugars.
Restricting fructose intake from sources like sugary beverages and processed foods is important due to its potent lipogenic effect. Replacing high-glycemic carbohydrates with lower-glycemic options, such as whole grains and high-fiber foods, helps stabilize blood sugar and insulin levels, suppressing the DNL-inducing signal. Diets rich in fiber, polyphenols, and healthy fats, like the Mediterranean eating pattern, have been shown to reduce DNL.
Physical activity provides a powerful counter-signal to the DNL pathway. Both aerobic exercise and resistance training enhance glucose uptake in muscles, reducing circulating glucose available for the liver to convert into fat. Exercise also promotes lipid oxidation, shifting metabolism away from fat storage toward fat utilization, which helps mitigate hepatic triglyceride accumulation independent of weight loss.