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Article

ER Unfolded Protein Response in Liver In Vivo Is Characterized by Reduced, Not Increased, De Novo Lipogenesis and Cholesterol Synthesis Rates with Uptake of Fatty Acids from Adipose Tissue: Integrated Gene Expression, Translation Rates and Metabolic Fluxes

by
Catherine P. Ward
1,
Lucy Peng
1,
Samuel Yuen
1,
Michael Chang
1,
Rozalina Karapetyan
1,
Edna Nyangau
1,
Hussein Mohammed
1,
Hector Palacios
1,
Naveed Ziari
1,
Larry K. Joe
2,
Ashley E. Frakes
2,
Mohamad Dandan
1,
Andrew Dillin
2 and
Marc K. Hellerstein
1,*
1
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 92093, USA
2
Department of Molecular and Cellular Biology, University of California, Berkeley, CA 92093, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(3), 1073; https://doi.org/10.3390/ijms23031073
Submission received: 21 December 2021 / Revised: 14 January 2022 / Accepted: 14 January 2022 / Published: 19 January 2022
(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response 2.0)
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Abstract

The unfolded protein response in the endoplasmic reticulum (UPRER) is involved in a number of metabolic diseases. Here, we characterize UPRER-induced metabolic changes in mouse livers in vivo through metabolic labeling and mass spectrometric analysis of lipid and proteome-wide fluxes. We induced UPRER by tunicamycin administration and measured synthesis rates of proteins, fatty acids and cholesterol, as well as RNA-seq. Contrary to reports in isolated cells, hepatic de novo lipogenesis and cholesterogenesis were markedly reduced, as were mRNA levels and synthesis rates of lipogenic proteins. H&E staining showed enrichment with lipid droplets while electron microscopy revealed ER morphological changes. Interestingly, the pre-labeling of adipose tissue prior to UPRER induction resulted in the redistribution of labeled fatty acids from adipose tissue to the liver, with replacement by unlabeled glycerol in the liver acylglycerides, indicating that the liver uptake was of free fatty acids, not whole glycerolipids. The redistribution of adipose fatty acids to the liver was not explicable by altered plasma insulin, increased fatty acid levels (lipolysis) or by reduced food intake. Synthesis of most liver proteins was suppressed under UPRER conditions, with the exception of BiP, other chaperones, protein disulfide isomerases, and proteins of ribosomal biogenesis. Protein synthesis rates generally, but not always, paralleled changes in mRNA. In summary, this combined approach, linking static changes with fluxes, revealed an integrated reduction of lipid and cholesterol synthesis pathways, from gene expression to translation and metabolic flux rates, under UPRER conditions. The reduced lipogenesis does not parallel human fatty liver disease. This approach provides powerful tools to characterize metabolic processes underlying hepatic UPRER in vivo.
Keywords: ER stress; proteostasis; UPR; lipid metabolism; metabolism ER stress; proteostasis; UPR; lipid metabolism; metabolism
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MDPI and ACS Style

Ward, C.P.; Peng, L.; Yuen, S.; Chang, M.; Karapetyan, R.; Nyangau, E.; Mohammed, H.; Palacios, H.; Ziari, N.; Joe, L.K.; et al. ER Unfolded Protein Response in Liver In Vivo Is Characterized by Reduced, Not Increased, De Novo Lipogenesis and Cholesterol Synthesis Rates with Uptake of Fatty Acids from Adipose Tissue: Integrated Gene Expression, Translation Rates and Metabolic Fluxes. Int. J. Mol. Sci. 2022, 23, 1073. https://doi.org/10.3390/ijms23031073

AMA Style

Ward CP, Peng L, Yuen S, Chang M, Karapetyan R, Nyangau E, Mohammed H, Palacios H, Ziari N, Joe LK, et al. ER Unfolded Protein Response in Liver In Vivo Is Characterized by Reduced, Not Increased, De Novo Lipogenesis and Cholesterol Synthesis Rates with Uptake of Fatty Acids from Adipose Tissue: Integrated Gene Expression, Translation Rates and Metabolic Fluxes. International Journal of Molecular Sciences. 2022; 23(3):1073. https://doi.org/10.3390/ijms23031073

Chicago/Turabian Style

Ward, Catherine P., Lucy Peng, Samuel Yuen, Michael Chang, Rozalina Karapetyan, Edna Nyangau, Hussein Mohammed, Hector Palacios, Naveed Ziari, Larry K. Joe, and et al. 2022. "ER Unfolded Protein Response in Liver In Vivo Is Characterized by Reduced, Not Increased, De Novo Lipogenesis and Cholesterol Synthesis Rates with Uptake of Fatty Acids from Adipose Tissue: Integrated Gene Expression, Translation Rates and Metabolic Fluxes" International Journal of Molecular Sciences 23, no. 3: 1073. https://doi.org/10.3390/ijms23031073

APA Style

Ward, C. P., Peng, L., Yuen, S., Chang, M., Karapetyan, R., Nyangau, E., Mohammed, H., Palacios, H., Ziari, N., Joe, L. K., Frakes, A. E., Dandan, M., Dillin, A., & Hellerstein, M. K. (2022). ER Unfolded Protein Response in Liver In Vivo Is Characterized by Reduced, Not Increased, De Novo Lipogenesis and Cholesterol Synthesis Rates with Uptake of Fatty Acids from Adipose Tissue: Integrated Gene Expression, Translation Rates and Metabolic Fluxes. International Journal of Molecular Sciences, 23(3), 1073. https://doi.org/10.3390/ijms23031073

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