Mammalian cells possess intricate mechanisms to adapt to malnutrition and starvation, with de novo lipogenesis (DNL) emerging as a pivotal pathway during stress. This thesis explores the regulation of lipid metabolism under nutrient stress, focusing on the interplay between Sirtuin 2 (SIRT2) and Acetyl-CoA Synthetase 2 (ACSS2). In Chapter 1, I provide an overview of acetyl-CoA's role in lipogenesis, highlighting its various sources and use in fatty acid synthesis and histone acetylation. Specifically, I explore the regulatory roles of ACSS2 and SIRT2 in lipogenesis, laying the foundation for understanding how cells manage nutrient stress, particularly amino acid deficiency. Chapter 2 explores how SIRT2, ACSS2, and lipid metabolism interact during times of nutrient stress, particularly amino acid deficiency We reveal a novel mechanism wherein SIRT2 catalyzes the deacetylation of ACSS2 at lysine residue K271, resulting in ubiquitination and degradation of ACSS2 by the proteasome. Substitution of K271 leads to reduced ubiquitination of ACSS2, higher levels of ACSS2 protein, and enhanced lipogenesis, revealing a cellular mechanism for the efficient regulation of lipogenesis under nutrient stress. In Chapter 3, we establish a nuclear role for the SIRT2-ACSS2 axis. Through qPCR analysis and functional assays, our study demonstrates that SIRT2 knockdown elevates the expression of key lipogenic genes, Fatty Acid Synthase (FASN) and Acetyl-CoA Carboxylase Alpha (ACACA). Moreover, inhibition of ACSS2 attenuates the upregulation of FASN induced by SIRT2 depletion, indicating a functional link between SIRT2, ACSS2, and FASN expression. These results are important in the field of cancer biology, as changes in FASN expression due to acetate supplementation closely resemble those caused by SIRT2 modulation in different cancer cell types.