Basal re-esterification finetunes mitochondrial fatty acid utilization
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Date
2023-05
Publication Type
Journal Article
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yes
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Abstract
Objective: Emerging evidence suggest the existence of constant basal lipolysis and re-esterification of a substantial fraction of thus liberated fatty acids. In stimulated lipolysis, the re-esterification is proposed to be a protective mechanism against lipotoxicity; however, the role of the lipolysis coupled to re-esterification under basal conditions has not been deciphered. Methods: We used adipocytes (in vitro differentiated brown and white adipocytes derived from a cell line or primary SVF culture) to study the effect of inhibition of re-esterification by pharmacological DGAT1 and DGAT2 inhibitors alone or in combination. We then evaluated cellular energetics, lipolysis flux, and lipidomic parameters along with mitochondrial properties and fuel utilization. Results: In adipocytes, DGAT1 and 2 mediated re-esterification is a moderator of fatty acid oxidation. Combined inhibition of both DGATs (D1+2i) increases oxygen consumption, which is largely due to enhanced mitochondrial respiration by lipolysis-derived fatty acids (FAs). Acute D1+2i selectively affects mitochondrial respiration without affecting the transcriptional homeostasis of genes relevant to mitochondrial health and lipid metabolism. D1+2i enhances the mitochondrial import of pyruvate and activates AMP Kinase to counteract CPT1 antagonism, thus facilitating the mitochondrial import of fatty acyl-CoA. Conclusions: These data implicate the process of re-esterification in the regulation of mitochondrial FA usage and uncover a mechanism of FAO regulation via crosstalk with FA re-esterification.
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published
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Journal / series
Volume
71
Pages / Article No.
101701
Publisher
Elsevier
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Subject
Adipose tissue; Lipolysis; Re-esterification; DGAT1; DGAT2; Fatty acid oxidation; Lipidomics
Organisational unit
08839 - Zamboni, Nicola (Tit.-Prof.)
03819 - Wolfrum, Christian (ehemalig) / Wolfrum, Christian (former)
02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich