The regulation of lipid storage in fat tissue is important for systemic homeostasis of energy metabolism, which is tightly associated with many diseases, like diabetes, fatty liver, cardiovascular disease and cancer. Lipid droplet, the specific organelle for lipid storage, has many functions and crosstalk with other organelles. While, mechanisms regulating lipid storage and lipid droplet homeostasis in vivo are not completely understood. The coordination between lipid droplet and other organelles are far from clear.
Recently, a research team led by Prof. HUANG Xun from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences revealed that NAD kinase (NADK) , which phosphorylates NAD+ to produce NADP+, regulates lipid storage and mitochondrial metabolism in fat tissue through supporting de novo lipogenesis. Although cellular NAD+ level depletion has been well-known as a hallmark of aging, the cellular and physiological function of NADK is largely unknown. This study was published in Cell Reports journal (https://doi.org/10.1016/j.celrep.2021.110157).
To identify new regulators of lipid storage in vivo, the researchers performed an RNAi screen in Drosophila fat tissue. They found knockdown of NADK causes severe lipid storage defect in fat tissue. NADK is important for maintaining the level of NADPH, which is an important reducing equivalent for fatty acid synthesis. Furthermore, NADK also regulates cellular metabolism and mitochondrial mass. Mitochondrial mass is reduced and mitochondrial metabolism is impaired in fat tissue of NADK RNAi.
Knockdown of FASN1, which encodes fatty acid synthase, exhibits the similar effect as NADK RNAi, suggesting that those changes are caused by lipogenesis blockage. Mechanistically, the elevated acetyl-CoA and subsequent PGC-1α acetylation and decreased mitochondrion-specific phospholipid cardiolipin synthesis are responsible for the reduced mitochondrial mass in NADK RNAi and FASN1 RNAi.
Taken together, NADK- and FASN1-mediated fatty acid synthesis coordinates lipid storage and mitochondrial function.
Working model of NADK regulating lipid storage and mitochondrial metabolism through fatty acid synthesis (Image by IGDB)
Dr. HUANG Xun
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences