From Food to Genes: Transcriptional Regulation of Metabolism by Lipids and Carbohydrates

Abstract

Lipids and carbohydrates regulate gene expression by means of molecules that sense these macronutrients and act as transcription factors. The peroxisome proliferator-activated receptor (PPAR), activated by some fatty acids or their derivatives, and the carbohydrate response element binding protein (ChREBP), activated by glucose-derived metabolites, play a key role in metabolic homeostasis, especially in glucose and lipid metabolism. Furthermore, the action of both factors in obesity, diabetes and fatty liver, as well as the pharmacological development in the treatment of these pathologies are indeed of high relevance. In this review we present an overview of the discovery, mechanism of activation and metabolic functions of these nutrient-dependent transcription factors in different tissues contexts, from the nutritional genomics perspective. The possibility of targeting these factors in pharmacological approaches is also discussed. Lipid and carbohydrate-dependent transcription factors are key players in the complex metabolic homeostasis, but these factors also drive an adaptive response to non-physiological situations, such as overeating. Possibly the decisive role of ChREBP and PPAR in metabolic regulation points to them as ideal therapeutic targets, but their pleiotropic functions in different tissues makes it difficult to “hit the mark”.

Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

“…We analyzed the expression of the most important transcription factors involved in lipid metabolism ( Figure 5 ). Based on the literature, we selected 17 genes coding for transcription factors [ 40 , 41 ]. Among them, 11 were dysregulated in the spinal cord of 60-day-old FUS +/+ mice compared to nTg controls.…”

The Reversible Carnitine Palmitoyltransferase 1 Inhibitor (Teglicar) Ameliorates the Neurodegenerative Phenotype in a Drosophila Huntington’s Disease Model by Acting on the Expression of Carnitine-Related Genes

“…Following dietary supplementation with coconut oil, which significantly worsens disease progression in HD flies as shown by behavioural analysis, CG6356 , dHNF4 , and CG10814 genes show upregulation, supporting the idea that fatty acid β-oxidation in the brain of the HD fly may play an important role in the neuronal decline typical of the HD disease. The observed upregulation of CG6356 , dHNF4 , and CG10814 genes might be due to the accumulation of lipid substrate in the cytosol [ 62 ], as their proteins are involved in carnitine transport [ 18 , 35 ] and lipid oxidation [ 37 ], respectively. As for CG10814 , we can summarise that it is upregulated in the HD brains and after coconut oil administration when the Drosophila phenotype is impaired, and downregulated by Teglicar treatment when symptoms of neurodegeneration improve.…”

Roles of Lipids in Health and Disease.

“…However, there is some controversy about the involvement of some nuclear receptors, despite PPARs being the preferred receptors for fatty acids, especially PUFAs. The PPARs carry out complementary and sometimes overlapping functions in the control of glucose and lipid metabolism in many tissues (Bravo-Ruiz et al, 2021). This could be one of the reasons why drugs targeting these factors have adverse effects in some cases and undetermined in others and still do not represent the coveted magic bullet against obesity and type 2 diabetes mellitus.…”

“…This could be one of the reasons why drugs targeting these factors have adverse effects in some cases and undetermined in others and still do not represent the coveted magic bullet against obesity and type 2 diabetes mellitus. Perhaps combinatorial strategies or supplementation with unsaturated fatty acids, which are natural ligands of the PPARs, could be safer and more effective drugs or nutraceuticals (Bravo-Ruiz et al, 2021).…”