TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis

The regulation of cellular phosphatidylethanolamine (PE) acyl chain composition is poorly understood. Here, the authors show that TLCD1 and TLCD2 proteins mediate the formation of monounsaturated fatty acid-containing PE species and promote the progression of non-alcoholic steatohepatitis. The fatty acid composition of phosphatidylethanolamine (PE) determines cellular metabolism, oxidative stress, and inflammation. However, our understanding of how cells regulate PE composition is limited. Here, we identify a genetic locus on mouse chromosome 11, containing two poorly characterized genes Tlcd1 and Tlcd2, that strongly influences PE composition. We generated Tlcd1/2 double-knockout (DKO) mice and found that they have reduced levels of hepatic monounsaturated fatty acid (MUFA)-containing PE species. Mechanistically, TLCD1/2 proteins act cell intrinsically to promote the incorporation of MUFAs into PEs. Furthermore, TLCD1/2 interact with the mitochondria in an evolutionarily conserved manner and regulate mitochondrial PE composition. Lastly, we demonstrate the biological relevance of our findings in dietary models of metabolic disease, where Tlcd1/2 DKO mice display attenuated development of non-alcoholic steatohepatitis compared to controls. Overall, we identify TLCD1/2 proteins as key regulators of cellular PE composition, with our findings having broad implications in understanding and treating disease.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
fatty-acids
liver
inflammation
phosphatidylcholine
ferroptosis
validation
metabolism
complex
choline
stress
Science & Technology - Other Topics

Palmgren, HenrikGothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology (author)
Glover, M. S. (author)
Ahnmark, A. (author)
Andreasson, A. C. (author)
Madeyski-Bengtson, K. (author)
Kawana, H. (author)
Allman, E. L. (author)
Kaper, DelaneyGothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xkapde (author)
Uhrbom, M. (author)
Andersson, L. (author)
Aasehaug, L. (author)
Forsstrom, J. (author)
Wallin, S. (author)
Ahlstedt, I. (author)
Leke, R. (author)
Karlsson, D. (author)
Gonzalez-King, H. (author)
Lofgren, L. (author)
Nilsson, R. (author)
Pellegrini, G. (author)
Kono, N. (author)
Aoki, J. (author)
Hess, S. (author)
Sienski, G. (author)
Pilon, Marc,1966Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xpilom (author)
Bohlooly-Y, M. (author)
Maresca, M. (author)
Peng, X. R. (author)
Göteborgs universitetInstitutionen för kemi och molekylärbiologi (creator_code:org_t)

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NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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