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Abstract
AT-1/SLC33A1 is a key member of the endoplasmic reticulum (ER) acetylation machinery, transporting acetyl-CoA from the cytosol into the ER lumen where acetyl-CoA serves as the acetyl-group donor for Nε-lysine acetylation. Dysfunctional ER acetylation, as caused by heterozygous or homozygous mutations as well as gene duplication events of AT-1/SLC33A1, has been linked to both developmental and degenerative diseases. Here, we investigate two models of AT-1 dysregulation and altered acetyl-CoA flux: AT-1S113R/+ mice, a model of AT-1 haploinsufficiency, and AT-1 sTg mice, a model of AT-1 overexpression. The animals display distinct metabolic adaptation across intracellular compartments, including reprogramming of lipid metabolism and mitochondria bioenergetics. Mechanistically, the perturbations to AT-1-dependent acetyl-CoA flux result in global and specific changes in both the proteome and the acetyl-proteome (protein acetylation). Collectively, our results suggest that AT-1 acts as an important metabolic regulator that maintains acetyl-CoA homeostasis by promoting functional crosstalk between different intracellular organelles.
Highlights
AT-1/SLC33A1 is a key member of the endoplasmic reticulum (ER) acetylation machinery, transporting acetyl-CoA from the cytosol into the ER lumen where acetyl-CoA serves as the acetyl-group donor for Nε-lysine acetylation
Histological assessment revealed that AT-1S113R/+ mice have increased propensity to liver steatosis, which could be documented by both hematoxylin and eosin (H&E) (Fig. 1b) and electron microscopy (Fig. 1c)
We previously reported that AT-1 sTg eat more than their WT littermates[10], and similar behavior was observed over the 4 weeks of highcarbohydrate diet (HCD) feeding (Fig. 1i), there was no increase in body weight (Fig. 1j), suggesting that the changes in lipid metabolism were not due to altered food intake
Summary
AT-1/SLC33A1 is a key member of the endoplasmic reticulum (ER) acetylation machinery, transporting acetyl-CoA from the cytosol into the ER lumen where acetyl-CoA serves as the acetyl-group donor for Nε-lysine acetylation. Changes in the intracellular acetyl-CoA flux caused by hypoactive or hyperactive AT-1 could conceivably influence phenotypes beyond the secretory pathway; in particular the metabolic effects of these genetic manipulations have yet to be defined. For this purpose, we examine the hepatic molecular signatures of AT-1S113R/+ mice[8], a model of AT-1 haploinsufficiency, and AT-1 sTg mice[10], a model of global AT-1 overexpression. The animals display distinct metabolic reprogramming across several intracellular compartments and pathways that is achieved through specific changes in both the proteome and the acetyl-proteome (protein acetylation). Our results suggest that AT-1 is an essential component of an intracellular communication network that promotes functional crosstalk between different cellular compartments and organelles to maintain acetyl-CoA homeostasis
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