Hepatic de novo lipogenesis pathway (DNL)

The **hepatic de novo lipogenesis pathway** refers to the series of biochemical reactions in which excess dietary carbohydrates are converted into fatty acids within hepatocytes. This process begins with acetyl-CoA generated from carbohydrate catabolism and proceeds through several enzymatically catalyzed steps—primarily involving acetyl-CoA carboxylase and fatty acid synthase—to produce saturated long-chain fatty acids such as palmitate. These newly synthesized fats can be stored in the liver or exported as triglycerides. In healthy individuals, this process helps maintain energy balance and glucose homeostasis. However, dysregulation—often driven by high sugar intake or insulin resistance—leads to increased fat accumulation in the liver (**hepatic steatosis**) and contributes significantly to conditions like nonalcoholic fatty liver disease (**NAFLD**), type 2 diabetes mellitus, metabolic syndrome, cardiovascular risk factors such as dyslipidemia and inflammation. Key transcriptional regulators include sterol regulatory element-binding protein 1c (**SREBP‐1c**) activated by insulin signaling and carbohydrate response element-binding protein (**ChREBP**) stimulated by carbohydrate intake; both upregulate expression of genes encoding critical enzymes for this synthetic route[1][2]. Pharmacological interventions aim at inhibiting pivotal steps within this cascade—for example using omega‐3 polyunsaturated fats that suppress DNL activity—or direct enzyme inhibitors under clinical investigation for NAFLD/NASH therapy.[6] Circulating levels of certain saturated/monounsaturated fats serve both as functional readouts ("biomarkers") for patient selection/monitoring efficacy during clinical trials.[5]

Other names

De novo lipogenesis (DNL)Hepatic DNLLiver fatty acid synthesis

Mechanisms involve inhibition or modulation of key enzymes such as acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1) to reduce hepatic lipid synthesis and accumulation.