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SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation
Abstract
In liver, the synthesis of cholesterol and fatty acids increases in response to cholesterol deprivation and insulin elevation, respectively. This regulatory mechanism underlies the adaptation to cholesterol synthesis inhibitors (statins) and high calorie diets (insulin). In nonhepatic cells, lipid synthesis is controlled by sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors whose active domains are released proteolytically to enter the nucleus and activate genes involved in the synthesis and uptake of cholesterol and fatty acids. SCAP (SREBP cleavage-activating protein) is a sterol-regulated escort protein that transports SREBPs from their site of synthesis in the endoplasmic reticulum to their site of cleavage in the Golgi. Here, we produced a conditional deficiency of SCAP in mouse liver by genomic recombination mediated by inducible Cre recombinase. SCAP-deficient mice showed an 80% reduction in basal rates of cholesterol and fatty acid synthesis in liver, owing to decreases in mRNAs encoding multiple biosynthetic enzymes. Moreover, these mRNAs failed to increase normally in response to cholesterol deprivation produced by a cholesterol synthesis inhibitor and to insulin elevation produced by a fasting–refeeding protocol. These data provide in vivo evidence that SCAP and the SREBPs are required for hepatic lipid synthesis under basal and adaptive conditions.
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Hepatic SREBP2 activity and cholesterol biosynthesis rate fall while fasting and rise greatly upon refeeding.
“Substantial evidence supports the conclusion that hepatic SREBP2 activity and cholesterol biosynthesis rate fall while fasting and rise greatly upon refeeding, indicating the existence of feeding-responsive signaling pathways upregulating hepatic cholesterol synthesis in the presence of dietary nutrition (Horton et al., 1998; Liang et al., 2002; Matsuda et al., 2001; Slakey et al., 1972).”
From GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis (2019) · cites this paper as Matsuda et al., 2001
The Results (page unavailable) report that fasting reduced hepatic SREBP-2 mRNA and cholesterol-synthesis target-gene mRNAs in mice; refeeding raised several target-gene mRNAs above their nonfasted levels. These findings support a feeding-responsive cholesterol-synthesis pathway, but the cited passage does not establish that SREBP-2 activity and the measured rate of cholesterol biosynthesis both fell during fasting and rose greatly upon refeeding. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAblation of Scap, Mbtps1, and Spring results in decreased cholesterol synthesis in isolated primary hepatocytes.
“Moreover, (iv) ablation of all 3 genes results in decreased cholesterol synthesis in isolated primary hepatocytes”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [31]
The Results (page unavailable in our copy) report that cholesterol synthesis fell by 84% in fresh primary hepatocytes from SCAP-disrupted mice. The paper does not report corresponding ablation experiments for Mbtps1 or Spring, so it supports only the Scap portion of the claim. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn plasma, total cholesterol and triglycerides are lower in all mice with the exception that triglycerides are largely unchanged in Spring LKO.
“In plasma, (iii) total cholesterol and triglycerides are lower in all mice with the only exception being that the latter is largely unchanged in Spring LKO.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [31]
The Results and Tables 1–2 report lower plasma cholesterol and triglycerides in SCAP-deficient mice, although the triglyceride difference narrows with fasting. The paper studies SCAP-deficient mice, not Spring LKO mice, so it does not support the claim about unchanged triglycerides in Spring LKO or the generalization to all the mice mentioned. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe phenotype of SPRINGKO cells is highly reminiscent of cells lacking SCAP and liver-specific Scap knockout mice.
“This is highly reminiscent of what is observed in cells lacking SCAP45 and in liver-specific Scap knockout mice46.”
From Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism (2020) · cites this paper as [46]
The effect of hepatic Spring silencing on SREBP2 is similar to the phenotype observed in liver- or intestine-specific Scap knockout mice.
“The effect on SREBP2 is similar to the phenotype observed in liver- or intestine-specific Scap knockout mice46,55”
From Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism (2020) · cites this paper as [46]
Hepatic SREBP2 activity and expression of its target genes such as HMGCR and LDLR fall while fasting and rise substantially upon refeeding.
“Abundant evidence demonstrates that hepatic SREBP2 activity and expression of its target genes such as HMGCR and LDLR fall while fasting and rise substantially upon refeeding”
From GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis (2019) · cites this paper as Matsuda et al., 2001
There exist feeding-responsive signaling pathways that upregulate hepatic cholesterol synthesis in the presence of dietary nutrition.
“Substantial evidence supports the conclusion that hepatic SREBP2 activity and cholesterol biosynthesis rate fall while fasting and rise greatly upon refeeding, indicating the existence of feeding-responsive signaling pathways upregulating hepatic cholesterol synthesis in the presence of dietary nutrition (Horton et al., 1998; Liang et al., 2002; Matsuda et al., 2001; Slakey et al., 1972).”
From GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis (2019) · cites this paper as Matsuda et al., 2001
Scap knockout mice show reduced nuclear SREBP accumulation and low cholesterol levels in serum and liver.
“Scap knockout mice show reduced nuclear SREBP accumulation and low cholesterol levels in serum and liver (Matsuda et al., 2001).”
From Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP (2017) · cites this paper as Matsuda et al., 2001
In the liver, cholesterol levels are lower in Scap and Spring mice, but unchanged in Mbtps1 mice.
“In the liver (i) cholesterol levels are lower in Scap and Spring mice, but unchanged in Mbtps1 mice”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [31]
Constitutive deletion of Mbtps1, Scap, or Spring leads to in utero lethality.
“Similarly, constitutive deletion of either Mbtps121, Scap31, or Spring10 leads to in utero lethality.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [31]
In the liver, triglyceride levels are lower in Scap, Mbtps1, and Spring mice.
“and (ii) triglyceride levels are lower in all three”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [31]
Ablation of Scap, Mbtps1, and Spring uniformly reduced the expression of Srebf1 and Srebf2 target genes.
“and (v) uniformly reduced the expression of Srebf1 and Srebf2 target genes”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [31]
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Metadata
- Authors
- Matsuda, M., Korn, B. S., Hammer, R. E., Moon, Y.-A., Komuro, R., Horton, J. D., Goldstein, J. L., Brown, M. S., & Shimomura, I.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2001-05-15
- Volume
- 15
- Issue
- 10
- Pages
- 1206-1216
- ISSN
- 0890-9369
- 1549-5477
- Cited by
- 303
- References
- 3
- Language
- en
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