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SREBP-regulated lipid metabolism: convergent physiology — divergent pathophysiology

Key Points

  • Sterol regulatory-element binding proteins (SREBPs) are transcription factors that regulate the expression of genes involved in lipid synthesis and function as key nodes of convergence and divergence within global biological signalling networks involved in various physiological and pathophysiological processes

  • Distinctive physiological roles of SREBPs have been established: SREBP1a is involved in global lipid synthesis and growth; SREBP1c is involved in fatty acid synthesis and energy storage; and SREBP2 is involved in cholesterol regulation

  • Trafficking between the endoplasmic reticulum, Golgi and nucleus are key events in the activation and regulation of SREBPs and involve factors that mediate cleavage, recycling and degradation

  • In states of energy abundance, AKT–mTOR–SREBP signalling by insulin and growth factors is the primary axis in anabolic metabolism, which produces biomass involved in nutrition, growth and cancer

  • SREBPs are involved in myriad cellular processes and pathologies such as reactive oxygen species generation, endoplasmic reticulum stress, apoptosis and autophagy; the underlying molecular mechanisms are complex and require further investigation

  • SREBP1 activation causes lipid-mediated cellular stress (lipotoxicity) that contributes to metabolic diseases such as obesity, diabetes mellitus, dyslipidaemia, hepatosteatosis and atherosclerosis, thereby further extending SREBP-related pathology to include inflammation and fibrosis in various organs

Abstract

Cellular lipid metabolism and homeostasis are controlled by sterol regulatory-element binding proteins (SREBPs). In addition to performing canonical functions in the transcriptional regulation of genes involved in the biosynthesis and uptake of lipids, genome-wide system analyses have revealed that these versatile transcription factors act as important nodes of convergence and divergence within biological signalling networks. Thus, they are involved in myriad physiological and pathophysiological processes, highlighting the importance of lipid metabolism in biology. Changes in cell metabolism and growth are reciprocally linked through SREBPs. Anabolic and growth signalling pathways branch off and connect to multiple steps of SREBP activation and form complex regulatory networks. In addition, SREBPs are implicated in numerous pathogenic processes such as endoplasmic reticulum stress, inflammation, autophagy and apoptosis, and in this way, they contribute to obesity, dyslipidaemia, diabetes mellitus, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, neurodegenerative diseases and cancers. This Review aims to provide a comprehensive understanding of the role of SREBPs in physiology and pathophysiology at the cell, organ and organism levels.

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Figure 1: The sterol regulatory element-binding protein pathway.
Figure 2: Physiological actions of insulin-induced gene proteins and their associated proteins.
Figure 3: Nutritional and growth signalling to sterol regulatory element- binding proteins.
Figure 4: Lipotoxicity mediated by sterol regulatory element-binding proteins.
Figure 5: Sterol regulatory element-binding protein regulation of tissue cholesterol and plasma LDL levels.

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Acknowledgements

The authors sincerely thank all their collaborators and laboratory members for their contributions to the work discussed in this Review. The authors are aware that there are considerable pieces of work on SREBPs that could not be included in this Review owing to lack of space. The authors acknowledge Enago for reviewing the English language in this Review before submission of the manuscript.

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H.S. and R.S. researched data for the article, made substantial contributions to discussions about the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Hitoshi Shimano or Ryuichiro Sato.

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Shimano, H., Sato, R. SREBP-regulated lipid metabolism: convergent physiology — divergent pathophysiology. Nat Rev Endocrinol 13, 710–730 (2017). https://doi.org/10.1038/nrendo.2017.91

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