Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues - PubMed (original) (raw)

Review

Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues

Ziyi Song et al. Nutrients. 2018.

Abstract

De novo lipogenesis (DNL) is a complex and highly regulated process in which carbohydrates from circulation are converted into fatty acids that are then used for synthesizing either triglycerides or other lipid molecules. Dysregulation of DNL contributes to human diseases such as obesity, type 2 diabetes, and cardiovascular diseases. Thus, the lipogenic pathway may provide a new therapeutic opportunity for combating various pathological conditions that are associated with dysregulated lipid metabolism. Hepatic DNL has been well documented, but lipogenesis in adipocytes and its contribution to energy homeostasis and insulin sensitivity are less studied. Recent reports have gained significant insights into the signaling pathways that regulate lipogenic transcription factors and the role of DNL in adipose tissues. In this review, we will update the current knowledge of DNL in white and brown adipose tissues with the focus on transcriptional, post-translational, and central regulation of DNL. We will also summarize the recent findings of adipocyte DNL as a source of some signaling molecules that critically regulate energy metabolism.

Keywords: ChREBP; FASN; LXR; SREBP; adipocyte; central regulation; de novo lipogenesis; insulin resistance; obesity; post-translation; thermogenesis; transcription.

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Conflict of interest statement

The authors declare no conflicts of interest with the contents of this article.

Figures

Figure 1

Figure 1

Transcriptional activation of de novo lipogenesis in adipocytes in response to high-sugar or high-fat diets. After the consumption of carbohydrates, a portion of the circulating glucose is taken by adipocytes through insulin-stimulated GLUT4, and then through glycolysis in the cytosol, glucose is converted to pyruvate, which is transported into mitochondria for further oxidation in the tricarboxylic acid (TCA) cycle. Citrate, an intermediate of the TCA cycle, is exported into cytosol and used as a substrate for de novo lipogenesis. Regulation of lipogenesis is mainly at the transcriptional level and carbohydrate response element-binding protein (ChREBP) plays a major role in adipocyte lipogenesis. Glucose metabolites generated during glycolysis activate ChREBP-α, which, together with Max-like protein X (MLX), binds to the carbohydrate response elements (ChoRE) in the promoters of target genes, including those encoding ATP-citrate lyase (ACLY), acetyl-CoA carboxylases 1 (ACC1), fatty acid synthase (FASN), stearoyl-CoA desaturase-1 (SCD1), and ChREBP-β. The induced ChREBP-β in turn further activates its target gene expression, which ultimately promotes the synthesis of fatty acids. Another lipogenic transcription factor sterol regulatory element-binding protein-1 (SREBP-1), induced by insulin at multiple levels, may play a minor role in adipocyte lipogenesis. Compared with carbohydrates, fat consumption inhibits de novo lipogenesis in adipocyte mainly through blocking the activation of ChREBP-β. FATP—fatty acid transport protein-1; IR—insulin receptor.

Figure 2

Figure 2

Systemic effects of lipokines produced by de novo lipogenesis in adipocytes. When de novo lipogenesis is increased in adipocytes by means of increasing glucose uptake, decreasing lipid chaperones, or others, some bioactive fatty acids such as palmitoleate and fatty acid ester of hydroxyl fatty acids (FAHFAs) are produced. As a product of SCD1 in adipocytes, palmitoleate functions to improve insulin sensitivity in skeletal muscle and liver, promote pancreatic β-cell proliferation, and inhibit lipid synthesis in the liver. Although it is unclear how FAHFAs are synthesized in adipocytes, these lipids have a function to stimulate adipocyte glucose uptake, intestinal glucagon-like peptide-1 (GLP-1) secretion and β-cell insulin secretion, and reduce inflammation in adipose tissues. The metabolically beneficial effects of palmitoleate and FAHFAs are probably through G protein-coupled receptor 120 (GPR120). In addition, FASN may produce some unknown lipid products in white adipocytes that function to inhibit white fat browning through neuronal circuit regulation. WAT—white adipose tissues.

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