Progress on Protein Post-translational Modification to Regulate Fatty Acid Synth
Posted by beauty33 on November 24th, 2019
A new project named as Post-translational regulation of lipogenesis via AMPK-dependent phosphorylation of insulin-induced gene was published in Nature Communications. This is achieved by Li Yu Research Group, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences.
The study found that the new mechanism for adenylate-activated protein kinase (AMPK) to increase the activity of the endoplasmic reticulum anchoring protein Insig by phosphorylation, thereby inhibiting the function of liver lipid synthesis, revealing that protein post-translational modification regulates fatty acid synthesis through ubiquitination and degradation pathways.
With the changes in lifestyle and diet, non-alcoholic fatty liver disease accounts for a growing proportion of the world, and its incidence has increased in recent years. Nonalcoholic fatty liver disease is closely related to the occurrence and development of major metabolic diseases such as type 2 diabetes, obesity and cardiovascular diseases. The increase in de novo synthesis of fatty acids in the liver plays an important role in the development of nonalcoholic fatty liver. AMPK is the main energy-sensing factor of eukaryotes. In the case of energy stress, it induces elevated levels of AMP: ATP and ADP: ATP in cells, which inhibits anabolism and promotes catabolism to bring energy to a steady state. As an important energy-sensing factor, AMPK regulates processes such as protein, fat and sugar metabolism. Metformin is the drug of choice for the treatment of type 2 diabetes in the clinic and can activate the AMPK to improve the body's glycolipid metabolism disorder. Metformin also has good effects in improving liver lipid deposition and reducing non-alcoholic fatty liver disease in humans, but its molecular mechanism still needs further clarification.
Li Yu team Ph.D. Han Yamei, Hu Zhimin and others constructed a diet-induced obese mouse model of metformin administration. By screening differential proteins in mouse liver, it was found that metformin treatment can significantly increase liver cell anchors while activating AMPK. The protein levels of Insig-1 and Insig-2, which are located in the endoplasmic reticulum, are inversely related to the triglyceride content in the liver. Further studies have found that AMPK can phosphorylate Insig, inhibit the interaction between Insig and E3 ubiquitin ligase gp78, increase the protein stability by inhibiting the level of Insig ubiquitination and proteasome degradation, and then inhibit SREBP-1. Shear activation reduces lipid synthesis gene expression and hepatocyte lipid accumulation. Protein mass spectrometry and biochemical analysis showed that the Thr222 locus mediates the effect of AMPK on the enhancement of Insig-1 activity and the inhibition of SREBP-1 cleavage and lipid synthesis gene expression levels. At the same time, the researchers found that overexpression of Insig-1 by adenovirus can alleviate the increase in liver lipid deposition caused by liver-specific AMPKα2 deficiency. These studies indicate that Insig is a novel target protein of AMPK and plays an important role in mediating the inhibition of hepatic lipid de novo synthesis by the metformin-AMPK signaling pathway.
Recently, Li Yu team discovered that the new metabolic factor CREBZF can sense insulin signaling, and by inhibiting the transcription level of Insig, insulin can play a role in promoting liver lipid synthesis, thus revealing the scientific problem of why selective insulin resistance occurs in the liver (Zhang F, et al, Hepatology, 2018); In addition, studies have found that AMPK inhibits liver lipid synthesis by phosphorylating SREBP (Li Y, et al, Cell Metabolism, 2011). Under physiological conditions, these complex nutrient-sensing mechanisms and metabolic regulation pathways can effectively maintain the homeostasis of lipid metabolism in energy-deficient or adequate conditions; however, under the conditions of long-term obesity and overnutrition, these networks of metabolic regulatory molecules are blocked. Or disorder, causing imbalance of liver lipid metabolism and dysfunction, can lead to nonalcoholic fatty liver, insulin resistance and type 2 diabetes.
These suggest that CREBZF and AMPK-mediated Insig transcriptional regulation and post-translational modification play a key role in lipid metabolism, providing a new therapeutic strategy for the clinical treatment of nonalcoholic fatty liver.
Creative Proteomics has gradually developed into an integrated company that provides proteomics, metabolomics, glycomics, and bioinformatics analysis services to researchers in the pharmaceutical, biotechnology, agriculture and nutrition industries, as well as academic and government organizations.Also See: Liver Lipid, Fatty Liver, Post Translational, Lipid Synthesis, Synthesis, Protein, Liver
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