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Cited by 59Cholesterol and Lipid MetabolismLipid metabolism and disordersRenin-Angiotensin System Studies

The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index; none of the 62 sources its claims cite is checked for support yet.

(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis

Open access
Ren, Liwei, Sun, Yuan, Lu, Hong, Ye, Dien, Han, Lijuan, Wang, Na, Daugherty, Alan, Li, Furong, Wang, Miaomiao, Su, Fengting, Tao, Wenjun, Sun, Jie, Zelcer, Noam, Mullick, Adam E., Danser, A.H. Jan, Jiang, Yizhou, He, Yongcheng, Ruan, Xiongzhong, Lu, Xifeng·2018·Circulation Research
DOI 10.1161/circresaha.117.312422PMC PMC6309662
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Abstract

Rationale: An elevated level of plasma LDL (low-density lipoprotein) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDLR (LDL receptor) and SORT1 (sortilin-1), independently of the renin–angiotensin system. Objectives: To investigate the physiological role of (P)RR in lipid metabolism in vivo. Methods and Results: We used N-acetylgalactosamine modified antisense oligonucleotides to specifically inhibit hepatic (P)RR expression in C57BL/6 mice and studied the consequences this has on lipid metabolism. In line with our earlier report, hepatic (P)RR silencing increased plasma LDL-C (LDL cholesterol). Unexpectedly, this also resulted in markedly reduced plasma triglycerides in a SORT1-independent manner in C57BL/6 mice fed a normal- or high-fat diet. In LDLR-deficient mice, hepatic (P)RR inhibition reduced both plasma cholesterol and triglycerides, in a diet-independent manner. Mechanistically, we found that (P)RR inhibition decreased protein abundance of ACC (acetyl-CoA carboxylase) and PDH (pyruvate dehydrogenase). This alteration reprograms hepatic metabolism, leading to reduced lipid synthesis and increased fatty acid oxidation. As a result, hepatic (P)RR inhibition attenuated diet-induced obesity and hepatosteatosis. Conclusions: Collectively, our study suggests that (P)RR plays a key role in energy homeostasis and regulation of plasma lipids by integrating hepatic glucose and lipid metabolism.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Hepatic (P)RR inhibition in mice reduces ACC and PDH protein abundance, reprogramming lipid metabolism toward decreased lipid synthesis and increased fatty acid oxidation. This lowers plasma triglycerides and hepatic lipids, attenuates diet-induced obesity and hepatosteatosis, and improves glycemic control, while plasma cholesterol effects depend on LDLR/SORT1 status.

Key findings

  • GalNAc-modified antisense oligonucleotide at 3.0 mg kg−1 wk−1 silenced hepatic (P)RR without affecting heart, kidney, intestine, spleen, or adipose tissues. In normal-diet C57BL/6 mice, this increased plasma cholesterol in IDL/LDL fractions and reduced plasma triglycerides and hepatic VLDL secretion; in high-fat diet (HFD) mice, plasma cholesterol was 3- to 4-fold higher at 1 week but normalized by 2 weeks, with plasma and VLDL triglycerides lower and plasma LPL activity unchanged.
  • hSORT1 overexpression reversed the (P)RR inhibition–induced increase in plasma cholesterol but did not prevent the reduction in plasma triglycerides, indicating a SORT1-independent effect on triglycerides. In PCSK9 D377Y–injected and LDLR−/− mice, hepatic (P)RR inhibition reduced plasma cholesterol and triglycerides independent of diet and also reduced hepatic lipid levels.
  • In C57BL/6 mice fed HFD for 14 weeks, hepatic (P)RR inhibition attenuated diet-induced obesity, lowered fat mass without affecting lean mass, reduced liver and white adipose tissue size, prevented abnormal hepatic lipid deposition, reduced plasma leptin, improved glucose tolerance and lowered plasma insulin, and increased oxygen consumption and 24-hour respiratory quotient.
  • Mechanistically, RNA sequencing identified 199 upregulated and 202 downregulated genes, and proteomics identified 191 downregulated and 116 upregulated proteins. ACCα/β, PDHA, and PDHB protein levels were reduced by ≈40% to 60%; basal oxygen consumption rate increased by ≈50% in mouse primary hepatocytes and ≈30% in HepG2 cells, and long-chain fatty acid accounted for >40% of oxidized fuels after (P)RR inhibition versus ≈20% to 30% in controls.

Methods

  • Hepatic (P)RR was inhibited with N-acetylgalactosamine–modified antisense oligonucleotides in C57BL/6 mice fed normal or high-fat diets; additional experiments used PCSK9 D377Y adeno-associated virus–injected mice, LDLR−/− mice, and hSORT1 overexpression.
  • Main comparisons were saline, G-control, and G-(P)RR groups. Analyses included plasma lipid/lipoprotein profiling, LDL clearance, VLDL secretion, LPL activity, RNA sequencing, quantitative proteomics, qPCR, metabolite measurements, primary mouse hepatocytes, HepG2 cells, EchoMRI, metabolic cages, and histology.
  • The paper states that detailed methods are available in the Online Data Supplement.

Limitations

  • Stated: the post-transcriptional regulation of ACC and PDH is not well understood; the (P)RR inhibition–induced reduction in PDH was not rescued by autophagy, lysosome, or proteasome inhibitors, and its mechanism remains unsolved, as does the mechanism for SORT1. The authors also note it is unknown whether inhibiting (P)RR in both adipose tissue and liver would provide additional benefits.
  • Evident: the findings are based on mouse models and cell lines (primary mouse hepatocytes and HepG2), with no human in vivo validation reported; detailed experimental methods are relegated to the Online Data Supplement, limiting assessment from the main text alone.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1161/circresaha.117.312422

Cites

69 of 69 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 62 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Hepatic loss of (P)RR in mice results in a SORT1-dependent increase in plasma LDL levels.

    “We report that hepatic loss of (P)RR in mice results in a SORT1-dependent increase in plasma LDL levels”
    • Also stated in: § Methods and Results: · plain
      “In line with our earlier report, hepatic (P)RR silencing increased plasma LDL-C (LDL cholesterol).”
    Quote in the paperSubstantial claim
  • Findingown data

    Plasma LPL activity was not affected by hepatic (P)RR inhibition.

    “Importantly, plasma LPL (lipoprotein lipase) activity was not affected by hepatic (P)RR inhibition (Figure 2H).”
    Quote in the paperSubstantial claim
  • Findingown data

    In HFD-fed C57BL/6 mice, 1 week after (P)RR inhibition, plasma cholesterol levels were 3- to 4-fold higher than those in G-control-injected mice.

    “Like in ND-fed mice, 1 week after (P)RR inhibition, plasma cholesterol levels were 3- to 4- fold higher than those measured in N-acetylgalactosamine control antisense oligonucleotide (G-control)–injected mice (Figure 2A).”
    Quote in the paperSubstantial claim
  • Findingown data

    (P)RR inhibition significantly decreased plasma triglyceride concentrations.

    “Unexpectedly, (P)RR inhibition also significantly decreased plasma triglyceride concentrations (Figure 1D)”
    Quote in the paperSubstantial claim
  • Findingcitation

    Inhibiting (P)RR specifically reduced hepatic LDLR and SORT1 protein levels without affecting their transcript levels.

    “In line with our previous report, inhibiting the (P)RR specifically reduced hepatic LDLR and SORT1 protein levels without affecting their transcript levels (Online Figure IB).”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one. 38
  • The quote only partly states this claim. 2
  • Probably not a substantial claim. 30

  • It may state two separate claims as one.

    Findingown data

    At a dose of 3.0 mg kg−1 wk−1, G-(P)RR potently reduced (P)RR expression in liver but had no effects on its expression in other major organs.

    “At a dose of 3.0 mg kg−1 wk−1, N-acetylgalactosamine (P)RR antisense oligonucleotide (G-[P]RR) potently reduced (P)RR expression in liver, but had no effects on its expression in other major organs, including heart, kidney, intestine, spleen, and different adipose tissues (Online Figure IA and IC through IF).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The normalization of plasma cholesterol in HFD-fed mice contrasts with the sustained increase in plasma cholesterol levels in C57BL/6 mice fed ND.

    “This contrasts with the sustained increase in plasma cholesterol levels in C57BL/6 mice fed with ND (Online Figure IH).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Within 2 weeks, plasma cholesterol levels of G-(P)RR-injected HFD-fed mice normalized and were similar to those in saline-injected or G-control-injected mice.

    “Unexpectedly, within 2 weeks, plasma cholesterol levels of G-(P)RR–injected mice were normalized and similar to those in the saline-injected or G-control–injected mice (Figure 2A and 2C; Online Figure IG).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    (P)RR inhibition also increased cholesterol contents in the VLDL fraction and reduced cholesterol contents in the HDL fraction.

    “Notably, (P)RR inhibition also increased cholesterol contents in the VLDL fraction and reduced cholesterol contents in the HDL (high-density lipoprotein) fraction.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    (P)RR inhibition in HFD-fed mice reduced hepatic LDL clearance and VLDL secretion.

    “Nevertheless, (P)RR inhibition in HFD-fed mice reduced hepatic LDL clearance and VLDL secretion (Figure 2D and 2E).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Liver/body weight ratios of G-(P)RR-injected mice were significantly lower than those of G-control-injected mice and resembled the ratio of ND-fed C57BL/6 mice at the same age.

    “Liver/body weight ratios of G-(P)RR–injected mice were also significantly lower than that of G-control–injected mice and resembled the ratio of ND-fed C57BL/6 mice at the same age (Online Figure VB).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    (P)RR inhibition reduced VLDL secretion and plasma triglycerides.

    “we found that (P)RR inhibition reduced VLDL secretion and plasma triglycerides, likely as a consequence of reduced SORT1.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Inhibiting hepatic (P)RR increased oxygen consumption and 24-hour respiratory quotient of the mice.

    “Inhibiting hepatic (P)RR increased oxygen consumption and 24-hour respiratory quotient of the mice, implying increased catabolism of energy sources (Figure 5G).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Hepatic overexpression of hSORT1 in mice with (P)RR silencing was unable to prevent the reduction in plasma triglycerides, despite completely preventing the increase in plasma LDL-C.

    “However, hepatic overexpression of hSORT1 in mice with (P)RR silencing was unable to prevent the reduction in plasma triglycerides, despite completely preventing the increase in plasma LDL-C.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    (P)RR inhibition led to upregulation of 199 genes and downregulation of 202 genes.

    “We identified that (P)RR inhibition led to up- and downregulation of 199 genes and 202 genes, respectively (Online Table III).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    (P)RR inhibition improved glucose tolerance and lowered plasma insulin levels.

    “which also improved glucose tolerance and lowered plasma insulin levels (Online Figure VG and VH).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In HepG2 cells, (P)RR inhibition decreased acetyl-CoA levels, decreased cellular PDH activity, increased cellular pyruvate and medium lactate concentrations, and reduced cellular lipid levels.

    “Similarly, acetyl-CoA levels were decreased by (P)RR inhibition in HepG2 cells, combined with a decrease in cellular PDH activity, increased cellular pyruvate concentrations and medium lactate concentrations, and reduced cellular lipid levels (Online Figure VIIIC through VIIIG).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one. The quote only partly states this claim.

    Findingown data

    Both PDHA and PDHB were reduced by (P)RR inhibition.

    “Inhibiting hepatic (P) RR reduced ACC and PDH protein levels and consequently increases FA oxidation and reduces lipid synthesis, thus attenuating diet-induced obesity and liver steatosis, as well as improving glycemic controls in C57BL/6 mice.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Hepatic (P)RR inhibition attenuated diet-induced obesity and hepatosteatosis.

    “As a result, hepatic (P) RR inhibition attenuated diet-induced obesity and hepatosteatosis.”
    • Also stated in: § Hepatic (P)RR Inhibition Attenuated Diet-Induced Obesity and Improved Metabolic Disorders · plain
      “Hepatic (P)RR inhibition attenuated HFD-induced liver weight gain and prevented abnormal lipid deposition in the liver (Figure 5E and 5F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The (P)RR knockdown-induced reduction in ACCα/β protein abundance was partially reversed by bafilomycin A1, but was not affected by 3-methyladenine or MG-132.

    “The (P)RR knockdown–induced reduction in ACCα/β protein abundance was partially reversed by the lysosome inhibitor bafilomycin A1, but was not affected by the autophagy inhibitor 3-methyladenine or the proteasome inhibitor MG-132 (Online Figure VIIIB)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    G-(P)RR-injected mice consumed slightly less food than saline- or G-control-injected mice, but when corrected for body weight, their food consumption was higher.

    “G-(P)RR–injected mice consumed slightly less food than saline or G-control–injected mice, but when corrected for their body weight, their food consumption was actually higher (Online Figure VJ)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Inhibiting (P)RR significantly increased basal oxygen consumption rate by ≈50% in mouse primary hepatocytes and ≈30% in HepG2 cells.

    “As expected, inhibiting the (P)RR significantly increased basal oxygen consumption rate by ≈50% in mouse primary hepatocytes (Figure 6G) and ≈30% in HepG2 cells (Online Figure VIIIH)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Mice in which hepatic (P)RR was inhibited had smaller adipocytes in inguinal white adipose tissues but normal brown adipose tissue weight.

    “Moreover, mice in which hepatic (P)RR was inhibited had smaller adipocytes in inguinal white adipose tissues (Online Figure VC), but normal brown adipose tissues weight (Figure 5D).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Inhibiting hepatic (P)RR lowered fat weight but did not affect lean mass weight.

    “Body composition analyses using EchoMRI revealed that inhibiting hepatic (P)RR lowered fat weight of the mice, but did not affect the weight of lean mass (Figure 5B; Online Figure VA).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingcitation

    LDLR protein abundance was decreased by (P)RR inhibition, validating the effectiveness of the proteomic approach to identify proteins with altered abundance.

    “As reported previously, LDLR protein abundance was decreased by (P)RR inhibition (Online Table IV), validating the effectiveness of this approach to identify proteins with altered abundance.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingreasoning

    In livers of (P)RR-silenced mice, (P)RR inhibition reduces acetyl-CoA production from glucose, diminishes FA synthesis, and increases FA oxidation.

    “We thus speculated that by reducing PDH protein abundance and activity, (P)RR inhibition would reduce acetyl-CoA production from glucose and consequently diminish FA synthesis and increase FA oxidation (Figure 7).50 Indeed, this is what we observe in the livers of (P)RR-silenced mice.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Hepatic (P)RR inhibition attenuated HFD-induced liver weight gain and prevented abnormal lipid deposition in the liver.

    “Hepatic (P)RR inhibition attenuated HFD-induced liver weight gain and prevented abnormal lipid deposition in the liver (Figure 5E and 5F).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    GWAS studies identified single-nucleotide polymorphisms mapping to 1p13.3 that are strongly associated with plasma LDL levels and coronary heart disease.

    “Recently, GWAS studies have identified single-nucleotide polymorphisms mapping to 1p13.3 that strongly associated with plasma LDL levels and coronary heart disease.14–19”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [14] Kathiresan S, Willer CJ, Peloso GM, Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009; 41: 56– 65. doi: 10.1038/ng.291. 19060906 PMC2881676 source
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    • cites [16] Linsel-Nitschke P, Heeren J, Aherrahrou Z, Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL-uptake and serum LDL levels which translates to the risk of coronary artery disease. Atherosclerosis. 2010; 208: 183– 189. doi: 10.1016/j.atherosclerosis.2009.06.034. 19660754 source
    • cites [17] Muendlein A, Geller-Rhomberg S, Saely CH, Winder T, Sonderegger G, Rein P, Beer S, Vonbank A, Drexel H. Significant impact of chromosomal locus 1p13.3 on serum LDL cholesterol and on angiographically characterized coronary atherosclerosis. Atherosclerosis. 2009; 206: 494– 499. doi: 10.1016/j.atherosclerosis.2009.02.040. 19380133 source
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      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisereasoning

    The assembly of VLDL particles depends on apo B100 production and cellular availability of triglycerides.

    “The assembly of VLDL particles depends on apo B100 production and cellular availability of triglycerides.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    VLDL particles are formed by lipidation of apo B100 in the endoplasmic reticulum and Golgi apparatus.

    “VLDL particles are formed by lipidation of apo (apolipoprotein) B100, the core protein of VLDL, in the endoplasmic reticulum and Golgi apparatus.3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Olofsson SO, Stillemark-Billton P, Asp L. Intracellular assembly of VLDL: two major steps in separate cell compartments. Trends Cardiovasc Med. 2000; 10: 338– 345. 11369260 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The (P)RR interacts with renin/prorenin at supraphysiological concentrations that are several orders of magnitude higher than (patho)physiological concentrations, questioning the physiological relevance of the (P)RR-(pro)renin interaction.

    “The (pro)renin receptor ([P]RR) interacts with renin/prorenin (denoted as [pro]renin) at supraphysiological concentrations that are even several orders of magnitude higher than (patho)physiological concentrations, questioning the physiological relevance of the (P)RR–(pro)renin interaction.24,25”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Batenburg WW, Lu X, Leijten F, Maschke U, Müller DN, Danser AH. Renin- and prorenin-induced effects in rat vascular smooth muscle cells overexpressing the human (pro)renin receptor: does (pro)renin-(pro)renin receptor interaction actually occur? Hypertension. 2011; 58: 1111– 1119. doi: 10.1161/HYPERTENSIONAHA.111.180737. 22025376 source
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  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisereasoning

    Plasma LDL levels are determined by the dynamic balance between hepatic VLDL secretion and LDL clearance.

    “Hence, plasma LDL levels are determined by the dynamic balance between hepatic VLDL secretion and LDL clearance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Overexpression of apo B100 results in increased VLDL secretion and plasma LDL levels in rabbits.

    “Overexpression of apo B100 results in increased VLDL secretion and plasma LDL levels in rabbits.7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Fan J, McCormick SP, Krauss RM, Taylor S, Quan R, Taylor JM, Young SG. Overexpression of human apolipoprotein B-100 in transgenic rabbits results in increased levels of LDL and decreased levels of HDL. Arterioscler Thromb Vasc Biol. 1995; 15: 1889– 1899. 7583569 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Loss-of-function LDLR mutations are associated with elevated plasma LDL levels and cardiovascular risk.

    “In line with this, loss-of-function LDLR mutations are associated with elevated plasma LDL levels and cardiovascular risk.11–13”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The activity of enzymes involved in de novo lipid biosynthesis affects VLDL assembly and secretion.

    “Similarly, the activity of enzymes involved in de novo lipid biosynthesis also affects VLDL assembly and secretion.8,9”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    LDL is primarily cleared from the circulation in the liver via the LDLR pathway.

    “LDL, which is derived by peripheral lipolysis of VLDL (very-low-density lipoprotein), is primarily cleared from the circulation in the liver via the LDLR (LDL receptor) pathway.1,2”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    SORT1 deficiency reduces cellular LDL uptake in vitro and LDL clearance in vivo.

    “whereas SORT1 deficiency reduces cellular LDL up-take in vitro and LDL clearance in vivo.22,23”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Strong A, Ding Q, Edmondson AC, Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism. J Clin Invest. 2012; 122: 2807– 2816. doi: 10.1172/JCI63563. 22751103 PMC3408750 source
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  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The (P)RR plays a role in Wnt/β-catenin signaling, vacuolar H+-ATPase integrity, and T-cell development independently of (pro)renin.

    “Recently, the (P)RR was reported to play a role in Wnt/β-catenin signaling pathway, vacuolar H+-ATPase integrity, and T-cell development, independently of (pro)renin.26–30”
    Quote in the paperNot a substantial claim0 of 5 sources checked
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  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    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”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Genetic mutations in apo B100 are associated with altered VLDL secretion and plasma LDL levels.

    “Accordingly, genetic mutations in apo B100 are associated with altered VLDL secretion and plasma LDL levels.4–6”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Hooper AJ, van Bockxmeer FM, Burnett JR. Monogenic hypocholesterolaemic lipid disorders and apolipoprotein B metabolism. Crit Rev Clin Lab Sci. 2005; 42: 515– 545. doi: 10.1080/10408360500295113. 16390683 source
    • cites [5] Innerarity TL, Mahley RW, Weisgraber KH, Bersot TP, Krauss RM, Vega GL, Grundy SM, Friedl W, Davignon J, McCarthy BJ. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hyper-cholesterolemia. J Lipid Res. 1990; 31: 1337– 1349. 2280177 source
    • cites [6] Young SG, Hubl ST, Smith RS, Snyder SM, Terdiman JF. Familial hypobetalipoproteinemia caused by a mutation in the apolipoprotein B gene that results in a truncated species of apolipoprotein B (B-31). A unique mutation that helps to define the portion of the apolipoprotein B molecule required for the formation of buoyant, triglyceride-rich lipoproteins. J Clin Invest. 1990; 85: 933– 942. doi: 10.1172/JCI114522. 2312735 PMC296513 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Impaired loading of triglycerides into nascent VLDL particles caused by mutations in MTP results in defective VLDL secretion.

    “For example, impaired loading of triglycerides into nascent VLDL particles, caused by mutations in the MTP (microsomal triglyceride carrier protein), results in defective VLDL secretion.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Sharp D, Blinderman L, Combs KA, Kienzle B, Ricci B, Wager-Smith K, Gil CM, Turck CW, Bouma ME, Rader DJ. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature. 1993; 365: 65– 69. doi: 10.1038/365065a0. 8361539 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Kjolby M, Andersen OM, Breiderhoff T, Fjorback AW, Pedersen KM, Madsen P, Jansen P, Heeren J, Willnow TE, Nykjaer A. Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metab. 2010; 12: 213– 223. doi: 10.1016/j.cmet.2010.08.006. 20816088 source
    • cites [22] Strong A, Ding Q, Edmondson AC, Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism. J Clin Invest. 2012; 122: 2807– 2816. doi: 10.1172/JCI63563. 22751103 PMC3408750 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Overexpressing SORT1 promotes ApoB degradation via an endolysosome-dependent route and reduces VLDL secretion and plasma triglyceride levels.

    “Overexpressing SORT1 promotes ApoB degradation via an endolysosome-dependent route and hence reduces VLDL secretion and plasma triglyceride levels.22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Strong A, Ding Q, Edmondson AC, Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism. J Clin Invest. 2012; 122: 2807– 2816. doi: 10.1172/JCI63563. 22751103 PMC3408750 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Overexpression of SORT1 increases LDL clearance and decreases plasma LDL levels.

    “Overexpression of SORT1 increases LDL clearance and decreases plasma LDL levels,16,21,22”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Linsel-Nitschke P, Heeren J, Aherrahrou Z, Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL-uptake and serum LDL levels which translates to the risk of coronary artery disease. Atherosclerosis. 2010; 208: 183– 189. doi: 10.1016/j.atherosclerosis.2009.06.034. 19660754 source
    • cites [21] Musunuru K, Strong A, Frank-Kamenetsky M, From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010; 466: 714– 719. doi: 10.1038/nature09266. 20686566 PMC3062476 source
    • cites [22] Strong A, Ding Q, Edmondson AC, Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism. J Clin Invest. 2012; 122: 2807– 2816. doi: 10.1172/JCI63563. 22751103 PMC3408750 source

  • It may state two separate claims as one.

    Interpretationreasoning

    Increased FA oxidation provides additional acetyl-CoA to compensate the increased energetic demand, which could explain the increased oxygen consumption observed in G-(P)RR-injected mice.

    “It is plausible that increased FA oxidation provides additional acetyl-CoA to compensate the increased energetic demand, which could also explain the increased oxygen consumption observed in G-(P)RR–injected mice.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    (P)RR is a novel modulator of LDL metabolism in vitro.

    “We recently reported that the (P)RR is a novel modulator of LDL metabolism in vitro.31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Lu X, Meima ME, Nelson JK, Sorrentino V, Loregger A, Scheij S, Dekkers DH, Mulder MT, Demmers JA, M-Dallinga-Thie G, Zelcer N, Danser AH. Identification of the (pro)renin receptor as a novel regulator of low-density lipoprotein metabolism. Circ Res. 2016; 118: 222– 229. doi: 10.1161/CIRCRESAHA.115.306799. 26582775 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    ACC is crucial in determining lipid storage and overall energy metabolism.

    “ACC is crucial in determining lipid storage and overall energy metabolism.37”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Tong L Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell Mol Life Sci. 2005; 62: 1784– 1803. doi: 10.1007/s00018-005-5121-4. 15968460 PMC11139103

  • The quote only partly states this claim.

    Interpretationreasoning

    The reduction in plasma cholesterol levels in LDLR-deficient mice by (P)RR inhibition may be explained by limited lipid availability for ApoB lipidation.

    “This may also explain why (P)RR inhibition even reduced plasma cholesterol levels in LDLR-deficient mice, in whom SORT1-dependent LDL clearance is impaired.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationreasoning

    (P)RR inhibition accelerates ACC degradation via lysosomes by upregulating HECTD1.

    “It is therefore conceivable that (P)RR inhibition accelerates ACC degradation via lysosomes by upregulating HECTD1.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    (P)RR inhibition reduces PDHB protein levels via a tyrosine-phosphorylation-dependent manner in mouse retina and human retinal pigment epithelium cells.

    “(P)RR inhibition has previously been reported to reduce PDHB protein levels via a tyrosine-phosphorylation–dependent manner in mouse retina and human retinal pigment epithelium cells.47”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Kanda A, Noda K, Ishida S. ATP6AP2/(pro)renin receptor contributes to glucose metabolism via stabilizing the pyruvate dehydrogenase E1 β subunit. J Biol Chem. 2015; 290: 9690– 9700. doi: 10.1074/jbc.M114.626713. 25720494 PMC4392269 source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    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”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [16] Linsel-Nitschke P, Heeren J, Aherrahrou Z, Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL-uptake and serum LDL levels which translates to the risk of coronary artery disease. Atherosclerosis. 2010; 208: 183– 189. doi: 10.1016/j.atherosclerosis.2009.06.034. 19660754 source
    • cites [20] Kjolby M, Andersen OM, Breiderhoff T, Fjorback AW, Pedersen KM, Madsen P, Jansen P, Heeren J, Willnow TE, Nykjaer A. Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metab. 2010; 12: 213– 223. doi: 10.1016/j.cmet.2010.08.006. 20816088 source
    • cites [21] Musunuru K, Strong A, Frank-Kamenetsky M, From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010; 466: 714– 719. doi: 10.1038/nature09266. 20686566 PMC3062476 source
    • cites [22] Strong A, Ding Q, Edmondson AC, Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism. J Clin Invest. 2012; 122: 2807– 2816. doi: 10.1172/JCI63563. 22751103 PMC3408750 source
    • cites [38] Teslovich TM, Musunuru K, Smith AV, Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010; 466: 707– 713. doi: 10.1038/nature09270. 20686565 PMC3039276 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    TRB3 controls ACC degradation under fasting conditions by coupling ACC to the E3 ligase COP1.

    “TRB3 (tribbles-related protein 3) has been reported to control ACC degradation under fasting conditions by coupling ACC to the E3 ligase COP1 (constitutive photomorphogenic protein 1).58”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Qi L, Heredia JE, Altarejos JY, Screaton R, Goebel N, Niessen S, Macleod IX, Liew CW, Kulkarni RN, Bain J, Newgard C, Nelson M, Evans RM, Yates J, Montminy M. TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science. 2006; 312: 1763– 1766. doi: 10.1126/science.1123374. 16794074 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationown data

    (P)RR inhibition regulates PDH abundance via an as yet unsolved mechanism.

    “This may suggest that (P)RR inhibition regulates PDH abundance via an as yet unsolved mechanism, as seems to be the case with SORT1 as well.31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Lu X, Meima ME, Nelson JK, Sorrentino V, Loregger A, Scheij S, Dekkers DH, Mulder MT, Demmers JA, M-Dallinga-Thie G, Zelcer N, Danser AH. Identification of the (pro)renin receptor as a novel regulator of low-density lipoprotein metabolism. Circ Res. 2016; 118: 222– 229. doi: 10.1161/CIRCRESAHA.115.306799. 26582775 source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    ACC catalyzes the formation of malonyl-CoA, an essential substrate for FA synthesis and a potent inhibitor of FA oxidation.

    “ACC catalyzes the formation of malonyl-CoA, an essential substrate for FA synthesis and a potent inhibitor of FA oxidation.36”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Foster DW. Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. J Clin Invest. 2012; 122: 1958– 1959. 22833869 PMC3366419

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    SORT1 deficiency reduces VLDL secretion and plasma triglycerides.

    “SORT1 deficiency reduces VLDL secretion and plasma triglycerides,20”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Kjolby M, Andersen OM, Breiderhoff T, Fjorback AW, Pedersen KM, Madsen P, Jansen P, Heeren J, Willnow TE, Nykjaer A. Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metab. 2010; 12: 213– 223. doi: 10.1016/j.cmet.2010.08.006. 20816088 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    ACC plays an essential role in regulating FA synthesis and degradation.

    “ACC plays an essential role in regulating FA synthesis and degradation.37”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Tong L Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell Mol Life Sci. 2005; 62: 1784– 1803. doi: 10.1007/s00018-005-5121-4. 15968460 PMC11139103

  • It may state two separate claims as one.

    Premisecitation

    Both ACCα and ACCβ interact with HECTD1.

    “and both ACCα and ACCβ have been reported to interact with HECTD1.59”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Rouillard AD, Gundersen GW, Fernandez NF, Wang Z, Monteiro CD, McDermott MG, Ma’ayan A. The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database (Oxford). 2016; 2016: baw100. 27374120 PMC4930834 source

  • It may state two separate claims as one.

    Interpretationreasoning

    Reduced PDH and ACC may contribute to increased FA oxidation and decreased lipid synthesis.

    “Thus, reduced PDH and ACC may contribute to increased FA oxidation and decreased lipid synthesis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    PDH is a ubiquitously expressed enzyme complex that catalyzes the conversion of pyruvate to acetyl-CoA, acting as a central node that links lipid metabolism, glucose metabolism, and the tricarboxylic acid cycle.

    “PDH is a ubiquitously expressed enzyme complex that catalyzes the conversion of pyruvate to acetyl-CoA,48,49 acting as a central node that links lipid metabolism, glucose metabolism, and the tricarboxylic acid cycle.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Patel MS, Nemeria NS, Furey W, Jordan F. The pyruvate dehydrogenase complexes: structure-based function and regulation. J Biol Chem. 2014; 289: 16615– 16623. doi: 10.1074/jbc.R114.563148. 24798336 PMC4059105 source
    • cites [49] Harris RA, Bowker-Kinley MM, Huang B, Wu P. Regulation of the activity of the pyruvate dehydrogenase complex. Adv Enzyme Regul. 2002; 42: 249– 259. 12123719 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    PDH is the enzyme responsible for converting pyruvate to acetyl-CoA and is a central metabolic node.

    “PDH is the enzyme responsible for converting pyruvate to acetyl-CoA and is a central metabolic node.35”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Sugden MC, Holness MJ. Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab. 2003; 284: E855– E862. doi: 10.1152/ajpendo.00526.2002. 12676647 source

  • It may state two separate claims as one.

    Interpretationown data

    By reducing protein abundance of PDH, (P)RR inhibition reduces pyruvate to acetyl-CoA conversion and therefore reduces cellular acetyl-CoA production from glucose.

    “Collectively, our results suggest that by reducing protein abundance of PDH, (P)RR inhibition reduces pyruvate to acetyl-CoA conversion and therefore reduces cellular acetyl-CoA production from glucose.”
    Quote in the paperSubstantial claim
56 of 56

  • The paper relies on this without support.

    The effects of (P)RR inhibition observed in mice are relevant to human metabolic disorders.

    “Taken together, our study highlights the potential of inhibiting hepatic (P)RR as a therapeutic treatment for metabolic disorders such as fatty liver diseases and familial hypercholesterolemia.”

  • The paper relies on this without support.

    The C57BL/6 mouse model of diet-induced obesity and hepatosteatosis is representative of human obesity and hepatosteatosis.

    “thus attenuating diet-induced obesity and liver steatosis, as well as improving glycemic controls in C57BL/6 mice.”
2 of 2

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Metadata

Authors
Ren, L., Sun, Y., Lu, H., Ye, D., Han, L., Wang, N., Daugherty, A., Li, F., Wang, M., Su, F., Tao, W., Sun, J., Zelcer, N., Mullick, A. E., Danser, A. H. J., Jiang, Y., He, Y., Ruan, X., & Lu, X.
Affiliations
  • University of Kentucky (US)
  • From the AstraZeneca-Shenzhen University Joint Institute of Nephrology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen University, China (L.R., Y.S., D.Y., L.H., N.W., M.W., F.S., W.T., J.S., X.R., X.L.); Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, Shenzhen, China (L.R., Y.S., F.L., X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine,...
Corresponding author
  • Ren, Liwei
  • Sun, Yuan
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-03-02
Volume
122
Issue
5
Pages
730-741
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.117.312422
PMC
PMC6309662
OpenAlex
W2782021489
Cited by
59
References
69
Citations by year
2026: 3 · 2025: 5 · 2024: 10 · 2023: 5 · 2022: 9 · 2021: 10 · 2020: 5 · 2019: 7 · 2018: 5
FWCI
2.95
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
Funders
  • National Natural Science Foundation of China (KQTD20140630100746562, 81,390,354, 81500667, 81270789, 81670702)
  • Natural Science Foundation of Guangdong Province
  • Top Institute Pharma (T2-301)
  • Shenzhen Peacock Plan (KQTD20140630100746562)
  • National Heart, Lung, and Blood Institute (K99HL127272, R01HL064388)
  • FP7 Ideas: European Research Council (617376)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
Keywords
prorenin receptor, hepatic lipid metabolism, diet-induced obesity, hepatic steatosis, LDL cholesterol, triglycerides, LDL receptor, SORT1, acetyl-CoA carboxylase, pyruvate dehydrogenase, fatty acid oxidation, hepatic lipid synthesis, energy homeostasis
MeSH terms
Prorenin Receptor, Sortilin, Acetyl-CoA Carboxylase, Animals, Cells, Cultured, Fatty Liver, Humans, Male, Mice, Inbred C57BL, Obesity, Pyruvate Dehydrogenase Complex, Receptors, Cell Surface, Gene Silencing, Hepatocytes, Adaptor Proteins, Vesicular Transport, Lipid Metabolism, Mice, Hep G2 Cells, Diet, High-Fat

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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