Genetic control of de novo lipogenesis: role in diet-induced obesity

Abstract

De novo lipogenesis (DNL) is a complex yet highly regulated metabolic pathway, and transcription factors such as liver X receptor (LXR), sterol regulatory element-binding protein-1c (SREBP-1c), and carbohydrate response element binding protein (ChREBP) exert significant control over the de novo synthesis of fatty acids. An increase in de novo lipogenesis (DNL) is an important contributor to increased fat mass, while a reduction in lipogenesis may be protective against the development of obesity. In this review, we explore fatty acid synthesis in the context of new insights gleaned from global and tissue-specific gene knockout mouse models of enzymes involved in fatty acid synthesis, namely acetyl-CoA carboxylase, fatty acid synthase, fatty acid elongase 6, and stearoyl-CoA desaturase 1. A disruption in fatty acid synthesis, induced by the deficiency of any one of these enzymes, affects lipid metabolism and in some cases may protect against obesity in a tissue and gene-specific manner, as discussed in detail in this review.

Figure 1

De novo lipogenesis occurs in both liver and adipose tissue and can be stimulated by high carbohydrate and high fat diets. Dietary, de novo synthesized, and adipose tissue-derived fatty acids are incorporated into triacylglycerol, packaged into VLDL particles and secreted by the liver. Fatty acids are hydrolyzed from triacylglycerol molecules in peripheral tissues such as adipose and muscle. DNL, de novo lipogenesis; VLDL, very low density lipoprotein. Color version of figure is available online.

Figure 2

Pathway of de novo synthesis of saturated and monounsaturated fatty acids and regulation of lipogenic genes by transcription factors (LXR, SREBP-1c and ChREBP). NADPH is required for fatty acid synthesis and three chemical reactions yield NADPH (inset). PGC-1β has been shown to coactivate LXR and SREBP-1c, as discussed in the text. ACL, ATP-citrate lyase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; ELOVL6, elongation of long-chain fatty acids family member 6 (elongase 6); SCD, stearoyl-CoA desaturase; LXR, liver X receptor; SREBP-1c, sterol regulatory element-binding protein 1c; ChREBP, carbohydrate response element binding protein; ME, malic enzyme; G6PD, glucose 6-phosphate dehydrogenase; PGD, Phosphogluconate dehydrogenase. Color version of figure is available online.

Figure 3

Summary of metabolic phenotypes of tissue-specific gene knockout mouse models discussed in detail in text: ACC1, FAS, and SCD1 liver knockout (LKO) models, ACC1 adipose tissue knockout (AKO), FAS hypothalamus knockout (HKO), and SCD1 skin knockout (SKO). ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; SCD, stearoyl-CoA desaturase; HC, high carbohydrate; HF, high-fat; DI, diet-induced. Color version of figure is available online.