From the Guidelines
Malate in well-fed conditions contributes to lipogenesis by enabling the generation of NADPH in the cytosol. This process is intricately linked with the daily rhythms in cellular processes, including mitochondrial functions such as respiration and nutrient utilization, which show daily rhythms in rodents and humans 1. The malate-aspartate shuttle plays a crucial role in this context, where under a fed state, liver mitochondria actively uptake malate into the matrix 1. Although the study 1 focuses on the diurnal rhythms and mitochondrial metabolite flux, it implies that malate's role in the cytosol, particularly in generating NADPH through the malate-pyruvate shuttle, is pivotal for lipogenesis.
- Key points to consider:
- The generation of NADPH in the cytosol is essential for lipogenesis as it provides the reducing power needed for fatty acid synthesis.
- In well-fed states, excess carbohydrates are converted to citrate in mitochondria, which then moves to the cytosol and is cleaved to acetyl-CoA and oxaloacetate.
- The oxaloacetate can be reduced to malate, completing the cycle that generates the NADPH required for converting acetyl-CoA into fatty acids.
- This metabolic pathway is upregulated when energy intake exceeds immediate needs, allowing for energy storage in the form of lipids. Given the emphasis on daily rhythms and mitochondrial functions in the provided study 1, it's clear that the metabolic processes, including those involving malate, are highly regulated and responsive to the fed or fasted state of the organism.
From the Research
Malate and Lipogenesis
- Malate in the well-fed state contributes to lipogenesis by enabling the generation of acetyl-CoA in the cytosol 2
- The citrate carrier (CiC) plays a crucial role in this process by transporting citrate from the mitochondria to the cytosol, where it can be converted to acetyl-CoA and oxaloacetate 2
- Acetyl-CoA is then used as a building block for fatty acid synthesis, which is a key component of lipogenesis
Role of Malate in Mitochondrial Metabolism
- Malate is also involved in the mitochondrial malate-citrate exchange, which links mitochondrial respiratory metabolism with cytosolic biosynthetic pathways 3
- The DICARBOXYLATE CARRIER 2 (DIC2) protein facilitates this exchange by importing malate into the mitochondria and exporting citrate to the cytosol 3
Regulation of Lipogenesis
- Lipogenesis is regulated by various factors, including dietary macronutrient content, with high-carbohydrate diets stimulating lipogenesis and high-fat diets inhibiting it 4
- The regulation of lipogenesis also involves the coordination of multiple metabolic pathways, including glycolysis, gluconeogenesis, and fatty acid synthesis 5