Identification of an alternative triglyceride biosynthesis pathway

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.