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Sort1, Encoded by the Cardiovascular Risk Locus 1p13.3, Is a Regulator of Hepatic Lipoprotein Export
Abstract
Recent genome-wide association studies (GWAS) have revealed strong association of hypercholesterolemia and myocardial infarction with SNPs on human chromosome 1p13.3. This locus covers three genes: SORT1, CELSR2, and PSRC1. We demonstrate that sortilin, encoded by SORT1, is an intracellular sorting receptor for apolipoprotein (apo) B100. It interacts with apoB100 in the Golgi and facilitates the formation and hepatic export of apoB100-containing lipoproteins, thereby regulating plasma low-density lipoprotein (LDL) cholesterol. Absence of sortilin in gene-targeted mice reduces secretion of lipoproteins from the liver and ameliorates hypercholesterolemia and atherosclerotic lesion formation in LDL receptor-deficient animals. In contrast, sortilin overexpression stimulates hepatic release of lipoproteins and increases plasma LDL levels. Our data have uncovered a regulatory pathway in hepatic lipoprotein export and suggest a molecular explanation for the cardiovascular risk being associated with 1p13.3.
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A sortilin knockout mouse with residual truncated sortilin expression, when fed a Western-type diet, had reduced VLDL production.
“It was previously reported that a sortilinknockout mouse that had some residual truncated sortilin expression (12), upon feeding with a Western-type diet, had reduced VLDL production (23).”
From Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism (2012) · cites this paper as [23]
An independently generated Sort1-/- mouse has a paradoxical reduction in APOB/VLDL secretion on a chow diet on both a wild-type and APOBEC1-/-;APOB Tg background.
“We further demonstrate that, consistent with a previously published report (23), an independently generated Sort1 -/-mouse has a paradoxical reduction in APOB/VLDL secretion on a chow diet on both a wild-type and APOBEC1 -/-;APOB Tg background.”
From Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism (2012) · cites this paper as [23]
Sortilin acts as an intracellular sorting receptor for APOB100 and facilitates release of nascent APOB100-containing lipoproteins from the liver.
“The underlying mechanism was traced to the ability of sortilin to act as intracellular sorting receptor for APOB100 and to facilitate release of nascent APOB100-containing lipoproteins from the liver (Kjolby et al., 2010; Musunuru et al., 2010).”
From The Pro-Neurotrophin Receptor Sortilin Is a Major Neuronal Apolipoprotein E Receptor for Catabolism of Amyloid-β Peptide in the Brain (2013) · cites this paper as Kjolby et al., 2010
In the liver, sortilin acts as a lipoprotein receptor controlling hepatic uptake and release of cholesterol-rich lipoproteins, explaining genome-wide association of SORT1 with plasma cholesterol levels and risk of myocardial infarction.
“In the liver, it acts as a lipoprotein receptor controlling hepatic uptake but also release of cholesterol-rich lipoproteins, explaining genome-wide association of the encoding gene SORT1 with plasma cholesterol levels and the risk of myocardial infarction2,3,7–9”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [3]
Sortilin is a 95-kDa type-1 transmembrane receptor expressed in various mammalian cell types, most notably in neurons of the central and peripheral nervous system and in hepatocytes in the liver.
“Sortilin is a 95-kDa type-1 transmembrane receptor expressed in various mammalian cell types, most notably in neurons of the central and peripheral nervous system and in hepatocytes in the liver1–3.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [3]
SORT1, located within the 1p13.3 region, is a novel regulator of LDL metabolism.
“Subsequent mechanistic studies revealed that SORT1 (sortilin-1), located within the 1p13.3 region, is a novel regulator of LDL metabolism.20–22”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [20]
Mice deficient for SORT1 display reduced VLDL secretion and triglyceride levels.
“Controversially, mice deficient for SORT1 also display reduced VLDL secretion and triglyceride levels.20,22”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [20]
hSORT1 overexpression reversed the (P)RR inhibition-induced increase in plasma cholesterol levels, primarily by decreasing cholesterol content in the VLDL and IDL/LDL fractions.
“Given that SORT1 itself is a clearance receptor for LDL,20–22 it is not surprising that hSORT1 overexpression reversed the (P) RR inhibition–induced increase in plasma cholesterol levels, primarily by decreasing the cholesterol content in the VLDL and IDL/LDL fractions (Figure 3A and 3B).”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [20]
SORT1 deficiency reduces VLDL secretion and plasma triglycerides.
“SORT1 deficiency reduces VLDL secretion and plasma triglycerides,20”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [20]
SORT1 is a hepatic clearance receptor for LDL that also regulates VLDL secretion and plasma triglycerides.
“SORT1 is a recently identified hepatic clearance receptor for LDL, which also regulates VLDL secretion and plasma triglycerides.16,20–22,38”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [20]
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Metadata
- Authors
- Kjolby, M., Andersen, O. M., Breiderhoff, T., Fjorback, A. W., Pedersen, K. M., Madsen, P., Jansen, P., Heeren, J., Willnow, T. E., & Nykjaer, A.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 12
- Issue
- 3
- Pages
- 213-223
- ISSN
- 1550-4131
- Cited by
- 269
- References
- 5
- Language
- en
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1086 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Funders
- Danish Agency for Science and Higher Education
- Lundbeckfonden
- Hjerteforeningen
- Deutsche Forschungsgemeinschaft
- Hartmann Fonden
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