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Identification of an alternative triglyceride biosynthesis pathway.

Gian-Luca McLelland1, Marta Lopez-Osias2, Cristy R C Verzijl3

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Summary

Researchers discovered a new pathway for synthesizing triacylglycerols (TAGs) in humans, involving proteins DIESL and TMX1, which is crucial for energy homeostasis and mitochondrial function.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Metabolic Regulation

Background:

  • Triacylglycerols (TAGs) are vital energy stores, but their dysregulation is linked to obesity and cardiac disease.
  • Diacylglycerol O-acyltransferases (DGAT1 and DGAT2) are the known human enzymes for TAG synthesis.
  • The existence of alternative TAG synthesis pathways in humans has been unexplored.

Purpose of the Study:

  • To investigate potential alternative pathways for triacylglycerol (TAG) synthesis in human cells.
  • To identify novel enzymes and regulators involved in TAG biosynthesis beyond DGAT1 and DGAT2.

Main Methods:

  • Disruption of the known diacylglycerol O-acyltransferase (DGAT) pathway in haploid human cells.
  • Utilizing iterative genetics to screen for alternative TAG-synthesizing systems.
  • Characterizing the function of identified proteins (DIESL and TMX1) using biochemical and cellular assays.
  • Expressing human DIESL in Escherichia coli to confirm its TAG synthesis capability.
  • Investigating the physiological role of DIESL in mouse models.

Main Results:

  • An alternative TAG synthesis pathway was identified, involving the acyltransferase DIESL (TMEM68) and its regulator TMX1.
  • TMX1 regulates DIESL activity at the endoplasmic reticulum; its absence leads to uncontrolled lipid droplet formation.
  • DIESL functions as an autonomous TAG synthase, capable of synthesizing TAGs even in bacteria.
  • DIESL synthesizes TAGs by utilizing membrane phospholipids and supports mitochondrial function during nutrient scarcity.
  • DIESL deficiency in mice impairs postnatal growth and energy balance.

Conclusions:

  • A novel, DGAT-independent pathway for TAG biosynthesis, mediated by DIESL and regulated by TMX1, has been discovered in humans.
  • This DIESL-driven pathway plays a critical role in cellular energy metabolism, particularly under conditions of lipid starvation.
  • The findings reveal DIESL as a key player in maintaining mitochondrial function and overall energy homeostasis, with implications for metabolic diseases.