a Schematic representation of reduced acetyl-CoA transport through AT-1 in the haploinsufficient AT-1 S113R/+ mice. Finally, the serum lipid profiles were not different between wild-type (WT) and AT-1 S113R/+ mice (Table 2), indicating that the steatosis was not associated with dyslipidemia.ĪT-1 S113R/+ show spontaneous steatosis while AT-1 sTg are resistant to diet-induced steatosis.
#Cystol had higher ph than er lumen free
Biochemical analysis revealed a ~60% increase in free acetyl-CoA available within the cytosol and a marked accumulation of fatty acids and triglycerides in the liver (Table 1). Importantly, the animals displayed no differences in food intake or body weight (Fig. Although observed with both regular (40.2% carbohydrate, 4.7% fat) and breeder (44.7% carbohydrate, 9% fat) diets, the steatosis was much more common in animals fed the breeder diet. Histological assessment revealed that AT-1 S113R/+ mice have increased propensity to liver steatosis, which could be documented by both hematoxylin and eosin (H&E) (Fig. 1a), resulting in a ~50% decrease in acetyl-CoA transport from the cytosol into the ER lumen 8. When taken together, 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.Īberrant AT-1 activity alters lipid metabolismĪT-1 S113R/+ mice are haploinsufficient for AT-1 activity (Fig. 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). For this purpose, we examine the hepatic molecular signatures of AT-1 S113R/+ mice 8, a model of AT-1 haploinsufficiency, and AT-1 sTg mice 10, a model of global AT-1 overexpression. 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. In this study, we investigate the outcomes of dysregulated AT-1 activity on intracellular acetyl-CoA homeostasis. Both cell-based and mouse-based experiments support the conclusion that AT-1 activity regulates ER proteostasis by maintaining the balance between quality control and the induction of reticulophagy 1, 2, 8, 9, 10, 11, 12, 13, 14. Mouse models of altered AT-1 expression are effective models of human AT-1-linked diseases 8, 9, 10. Gene duplications in AT-1/SLC33A1 have been identified in patients with autistic-like features, intellectual disability, and dysmorphic features heterozygous mutations in AT-1/SLC33A1 are associated with a familial form of spastic paraplegia, while homozygous mutations are associated with developmental delay and premature death 3, 4, 5, 6, 7. The acetyl-CoA transporter, AT-1 (also referred to as 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 1, 2. 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. 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). The animals display distinct metabolic adaptation across intracellular compartments, including reprogramming of lipid metabolism and mitochondria bioenergetics. Here, we investigate two models of AT-1 dysregulation and altered acetyl-CoA flux: AT-1 S113R/+ mice, a model of AT-1 haploinsufficiency, and AT-1 sTg mice, a model of AT-1 overexpression. 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. 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.
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