The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance

Individuals heterozygous for a loss-of-function variant in SCARB1 (P376L) have increased levels of plasma HDL-C.

“Individuals who are heterozygous for a loss-of-function variant in SCARB1 (P376L), the gene encoding SR-BI, have increased levels of plasma HDL-C (56).”

• cites [56] sourceSupported

Loss of the CCC complex leads to increased expression of several WASH subunits, including WASHC1.

“we have shown that loss of the CCC complex leads to increased expression of several WASH subunits, including WASHC1 (17).”

• cites [17] sourcePartly supported

  In “Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins” (page unavailable), the paper reports that loss of COMMD1 or COMMD6 reduced CCC core subunits and increased expression of the WASH component WASH1, also called WASHC1. It does not report increased expression of several WASH subunits; its mention of FAM21 concerns colocalization, not increased expression. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

The itinerary of PCSK9-LDLR to the lysosome is spatially separated from the LDLR recycling route.

“These data indicate that the itinerary of PCSK9-LDLR to the lysosome is spatially separated from the LDLR recycling route (11,23,63).”

• cites [11] sourcePartly supported

  The section “Retrieval and degradative functions of the endosome are spatially segregated” says that degradative and retrieval complexes occupy distinct endosomal subdomains, though it describes cargo segregation as a possibility. “The CCC complex” identifies LDLR as recycling cargo. The paper does not establish that PCSK9-bound LDLR specifically follows a spatially separate itinerary to the lysosome. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [23] sourceCould not verify

  The Abstract distinguishes endosomal recycling from lysosomal degradation, and the Results mention machinery involved in LDLR recycling, but neither addresses the itinerary of PCSK9-bound LDLR or its spatial relationship to the LDLR recycling route. Searches for PCSK9 and spatial separation found no passage making that comparison; no page numbers are available in our copy. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites [63] sourcePartly supported

  The ‘Cargo fate decisions at the endosome’ section (p. 4) describes recycling cargo being retrieved into tubular carriers rather than entering the degradative pathway, and the reference annotation (p. 35) identifies LDLR as a recycling cargo. The copy does not establish that PCSK9-bound LDLR follows a spatially separate itinerary to the lysosome. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Both LDL-C and HDL-C are elevated in patients with X-linked intellectual disability caused by mutations in CCDC22.

“both LDL-C and HDL-C are elevated in patients with X-linked intellectual disability caused by mutations in the gene encoding the CCC-complex component CCDC22 (16).”

• cites [16] Bartuzi, 2016, CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL, Nat Commun sourcePartly supported

  The Results section, “CCDC22 mutations are associated with hypercholesterolaemia” (page unavailable), reports elevated LDL cholesterol in patients with CCDC22-related X-linked intellectual disability. It reports elevated total cholesterol, but does not establish that HDL cholesterol is elevated in those patients. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

A patient with RSS with a homozygous hypomorphic WASHC5 allele has relatively high plasma HDL-C levels.

“plasma HDL-C levels were also reported to be relatively high in a patient with RSS with a homozygous hypomorphic WASHC5 allele (16).”

• cites [16] Bartuzi, 2016, CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL, Nat Commun sourcePartly supported

  The Results section (‘COMMD1 and WASH facilitate LDLR trafficking’; page unavailable) reports one RSS patient with a homozygous KIAA0196 mutation that reduced strumpellin levels, and gives the patient’s HDL-C as 1.5 mmol/L. It describes total and LDL cholesterol—not HDL-C—as elevated, so the characterization of HDL-C as ‘relatively high’ is not established by the paper. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Ectopic expression of CETP decreases total cholesterol levels in mice.

“In agreement with previous studies (33,34), ectopic expression of CETP decreased TC levels in mice (Figure 3B)”

• cites [33] sourceSupported
• cites [34] sourceCould not verify

  The Discussion describes SR-BI trafficking and biliary cholesterol secretion, not CETP expression or total cholesterol levels in mice. Searches for CETP ectopic expression and total cholesterol in mice found no passage addressing the attributed finding. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

The diminished surface levels of SR-BI accompanied by reduced selective hepatic HDL-CE uptake suggest that the functioning of SR-BI is dependent on the WASH complex.

“The diminished surface levels of SR-BI accompanied by reduced selective hepatic HDL-CE uptake suggest that the functioning of SR-BI-the main receptor for hepatic HDL-C uptake in mice (54, 55)-is dependent on the WASH complex.”

• cites [54] sourceSupported
• cites [55] sourceSupported

PCSK9 does not have an effect on hepatic LRP1 degradation in WT mice.

“although PCSK9 does not have an effect on hepatic LRP1 degradation in WT mice (17,37,38)”

• cites [17] sourcePartly supported

  In the hepatic CCC-complex ablation results (page unavailable), PCSK9-D377Y reduced hepatic LDLR protein expression but not LRP1 protein expression in WT mice. This supports no observed effect on LRP1 abundance under that condition, but the paper does not directly measure LRP1 degradation or establish the claim for PCSK9 generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [37] sourcePartly supported

  The Results section (‘PCSK9-mediated LDLR Degradation in the Liver Does Not Require LRP1’) reports that PCSK9 infusion did not affect hepatic LRP1 levels in WT mice, and the Discussion reiterates this finding. The paper reports protein levels, not a direct measurement of LRP1 degradation, so the claim is more specific than the evidence. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [38] sourcePartly supported

  The Discussion reports that hepatic LRP protein levels were not significantly different in wild-type mice parabiosed with PCSK9-overexpressing mice. This supports a lack of detectable effect on LRP abundance, but the passage does not establish that PCSK9 has no effect on LRP1 degradation specifically. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

The CCC complex is physically associated with the WASH complex through binding of CCDC93 and CCDC22 to WASHC2.

“the CCC complex is physically associated with the WASH complex through the binding of the CCC components CCDC93 and CCDC22 to the WASH subunit WASHC2 (FAM21) (5).”

• cites [5] sourceSupported

Hepatic ablation of Washc1 does not affect hepatic bile acid metabolism.

“However, these changes did not translate into aberrant biliary cholesterol and bile acid excretion nor in altered fecal neutral sterol and bile acid loss (Supplemental Figure 3, E-H).”

Hepatic ablation of Washc1 does not affect hepatic cholesterol synthesis.

“We found that hepatic Washc1 ablation did not affect hepatic cholesterol and TG contents, VLDL production, and whole-body cholesterol synthesis rates (Supplemental Figure 3, A-D).”

Hepatic ablation of Washc1 does not affect hepatic cholesterol content.

“We found that hepatic Washc1 ablation did not affect hepatic cholesterol and TG contents, VLDL production, and whole-body cholesterol synthesis rates (Supplemental Figure 3, A-D).”

Hepatic ablation of Washc1 does not affect biliary cholesterol excretion.

“However, these changes did not translate into aberrant biliary cholesterol and bile acid excretion nor in altered fecal neutral sterol and bile acid loss (Supplemental Figure 3, E-H).”

Hepatic ablation of Washc1 in chow-fed mice increases plasma LDL cholesterol.

“the cholesterol content of the LDL fraction separated by fast protein liquid chromatography (FPLC) was increased (Figure 2, C and D).”

Plasma HL levels are not different between Washc1 ΔHep and WT mice.

“we did not find any difference in plasma HL levels as measured by targeted proteomics (Figure 5B)”

Impaired endosomal LDLR recycling by loss of WASHC1 does not affect PCSK9-mediated LDLR degradation.

“Here, we demonstrate that impaired endosomal LDLR recycling by the loss of WASHC1 does not affect PCSK9-mediated LDLR degradation.”

Hepatic Washc1 depletion exacerbates hypercholesterolemia in PCSK9-induced hepatic LDLR deficiency.

“We found that hepatic Washc1 depletion exacerbated hypercholesterolemia in PCSK9-induced hepatic LDLR deficiency (Figure 4F).”

Total protein levels of LRP1 are reduced in WASH-deficient primary hepatocytes.

“In addition to the surface levels, the total protein levels of LDLR and LRP1 were also reduced in WASH-deficient primary hepatocytes (Figure 4, A and B).”

Hepatic expression of PCSK9 increases ApoA-I levels in the WASH/LDLR-deficient model.

“Hepatic expression of PCSK9 also increased ApoA-I levels in this model, while HDL-C levels were unchanged (Figure 4H).”

CETP expression normalizes the increased HDL particles in Washc1 ΔHep mice.

“CETP expression normalized the increased HDL particles in the Washc1 ΔHep mice (Figure 2C) compared with Washc1 ΔHep mice without CETP expression (Figure 3C)”

Plasma ApoB48 and ApoB100 levels are elevated in mice deficient for hepatic WASH and LDLR compared with mice lacking only hepatic LDLR.

“plasma ApoB48 and ApoB100 levels were elevated in mice deficient for hepatic WASH and LDLR compared with mice lacking only hepatic LDLR (Figure 4, H and I).”

In Washc1 ΔHep mice with CETP expression, ApoA-I levels are increased compared with WT mice.

“However, in Washc1 ΔHep , the LDL-C, HDL-C, as well as the apolipoproteins ApoB, Apo-AI, and ApoE levels were increased compared with WT mice (Figure 3, C and D).”

Hepatic inactivation of the WASH complex does not affect plasma triglyceride levels.

“Hepatic inactivation of the WASH complex increased TC without affecting TG levels (Figure 2A).”

WASHC1 deficiency accelerates LDLR proteolysis promoted by IDOL.

“However, WASHC1 deficiency does accelerate LDLR proteolysis promoted by IDOL.”

Washc1 ΔHep mice show an increase in HDL-C.

“Interestingly, however, we also found an increase in HDL-C in Washc1 ΔHep mice.”

WASHC1 deficiency increases LDLR proteolysis by IDOL.

“loss of WASHC1 accelerated IDOL-mediated LDLR degradation.”

In Washc1 ΔHep mice with CETP expression, ApoE levels are increased compared with WT mice.

“However, in Washc1 ΔHep , the LDL-C, HDL-C, as well as the apolipoproteins ApoB, Apo-AI, and ApoE levels were increased compared with WT mice (Figure 3, C and D).”

PCSK9 decreases total LDLR levels in WT and WASHC1-deficient cells.

“Immunoblots showed that PCSK9 decreased total LDLR levels in WT and WASHC1-deficient cells”

Hepatic WASHC1 deficiency reduces the abundance of all WASH components.

“hepatic WASHC1 deficiency strongly reduced the abundance of all WASH components (Figure 1, A and B)”

Washc1 ΔHep mice have increased plasma ApoB levels.

“we observed increased plasma levels of apolipoproteins ApoE and ApoB in Washc1 ΔHep mice compared with WT mice (Figure 2B).”

Loss of WASHC1 accelerates IDOL-mediated LDLR degradation.

“loss of WASHC1 accelerated IDOL-mediated LDLR degradation.”

No significant differences in the mRNA levels of SREBP-2 target genes Ldlr and Hmgcr were found in Washc1 ΔHep mice.

“No significant differences in the mRNA levels of the SREBP-2 target genes, such as Ldlr and Hmgcr, were found (Supplemental Table 1).”

Hepatic ablation of both WASH and CCC complexes does not further increase total plasma cholesterol levels compared with single knockouts.

“Hepatic ablation of both complexes did not further increase total plasma cholesterol levels when compared with hepatic Washc1 and Commd1 single-knockout mice (Figure 6B).”

Loss of hepatic WASH does not noticeably alter the morphology of Golgi, endoplasmic reticulum, or mitochondria.

“However, the loss of hepatic WASH did not noticeably alter the morphology of other organelles such as Golgi, endoplasmic reticulum, or mitochondria.”

Holoparticle uptake is not changed in hepatic WASH-deficient mice.

“whereas holoparticle uptake was not changed (Figure 5D).”

Hepatic expression of human CETP shifts cholesterol from HDL toward LDL in both Washc1 ΔHep and WT mice.

“Hepatic expression of human CETP resulted in the expected shift of cholesterol from HDL toward LDL in both Washc1 ΔHep and WT mice (Figure 3C).”

Loss of WASHC1 does not affect the degradation kinetics of LDLR by PCSK9.

“but loss of WASHC1 did not affect the degradation kinetics of LDLR by PCSK9 (Figure 7, B and C).”

Washc1 ΔHep mice have increased plasma ApoE levels.

“we observed increased plasma levels of apolipoproteins ApoE and ApoB in Washc1 ΔHep mice compared with WT mice (Figure 2B).”

Several LXR target genes, including Abcg5, Abcg8, and Cyp7a1, are decreased upon hepatic Washc1 depletion.

“Several liver X receptor (LXR) targets, including genes involved in biliary cholesterol secretion and bile acid synthesis (Abcg5, Abcg8, and Cyp7a1) were decreased upon hepatic Washc1 depletion compared to WT livers (Supplemental Table 1)”

Hepatic WASH ablation reduces surface levels of SR-BI in hepatocytes.

“We found the cell surface abundance of SR-BI to be markedly decreased in WASH-deficient hepatocytes compared with WT cells (Figure 5A).”

Selective HDL-CE uptake by Washc1 ΔHep livers is significantly decreased compared with WT livers.

“the difference reflecting selective HDL-CE uptake by Washc1 ΔHep livers was significantly decreased compared with WT livers (Figure 5E).”

Hepatic inactivation of the WASH complex increases total plasma cholesterol.

“Hepatic inactivation of the WASH complex increased TC without affecting TG levels (Figure 2A).”

Hepatic ablation of the WASH complex decreases the average size of lysosomes.

“Hepatic ablation of the WASH complex decreased the average size of the lysosomes (Figure 1, C and D).”

In the absence of the WASH complex, LRP1 levels are significantly decreased upon PCSK9 overexpression in mouse livers.

“we found that in the absence of the WASH complex, LRP1 levels were significantly decreased upon PCSK9 overexpression in mouse livers (Figure 4, C and D, and Supplemental Figure 4).”

3H-HDL-CE clearance is delayed upon hepatic WASH inactivation.

“However, 3 H-HDL-CE clearance was delayed upon hepatic WASH inactivation (Figure 5C).”

Overexpression of PCSK9 lowers hepatic LRP1 levels in Washc1 ΔHep mice.

“Our data also unexpectedly suggest that overexpression of PCSK9 lowers hepatic LRP1 levels in Washc1 ΔHep mice.”

Hepatic WASH ablation reduces selective uptake of HDL cholesterol into the liver.

“the difference reflecting selective HDL-CE uptake by Washc1 ΔHep livers was significantly decreased compared with WT livers (Figure 5E).”

In Washc1 ΔHep mice with CETP expression, HDL-C levels are increased compared with WT mice.

“However, in Washc1 ΔHep , the LDL-C, HDL-C, as well as the apolipoproteins ApoB, Apo-AI, and ApoE levels were increased compared with WT mice (Figure 3, C and D).”

The decrease in LRP1 levels upon PCSK9 overexpression in WASH-deficient livers is not caused by a decrease in Lrp1 mRNA levels.

“As shown in Figure 4E, this modest decrease in LRP1 levels was not caused by a decrease in Lrp1 mRNA levels.”

WASH is required for normal levels of LRP1 at the cell surface.

“we learned that WASH is also required for normal levels of LRP1 at the cell surface (Figure 4, A and B).”

In CETP-expressing Washc1 ΔHep mice, total cholesterol levels are significantly higher than in WT mice.

“but the TC levels were significantly higher in CETP-expressing Washc1 ΔHep mice compared with WT mice (Figure 3B).”

In Washc1 ΔHep mice with CETP expression, ApoB levels are increased compared with WT mice.

“However, in Washc1 ΔHep , the LDL-C, HDL-C, as well as the apolipoproteins ApoB, Apo-AI, and ApoE levels were increased compared with WT mice (Figure 3, C and D).”

Hepatic expression of PCSK9 does not change HDL-C levels in the WASH/LDLR-deficient model.

“Hepatic expression of PCSK9 also increased ApoA-I levels in this model, while HDL-C levels were unchanged (Figure 4H).”

Cell surface levels of LDLR are reduced in plasma membranes of WASH-deficient primary hepatocytes.

“We found that the levels of LDLR were reduced in the plasma membranes of WASH-deficient primary hepatocytes compared with WT cells (Figure 4, A and B).”

WASHC1 deficiency does not affect PCSK9-mediated LDLR degradation.

“loss of WASHC1 did not affect the degradation kinetics of LDLR by PCSK9 (Figure 7, B and C).”

PCSK9-D377Y expression blunts hepatic LDLR levels in both Washc1 ΔHep and WT mice.

“In both Washc1 ΔHep and WT mice, the expression of PCSK9-D377Y blunted hepatic LDLR levels (Figure 4C).”

Hepatic WASHC1 deficiency does not affect the mRNA levels of WASH subunits.

“without affecting the mRNA levels of these subunits”

HDL-CE clearance in hepatic WASH-deficient mice is significantly reduced compared with WT mice.

“we calculated plasma fractional catabolic rates and observed that HDL-CE clearance in hepatic WASH-deficient mice was significantly reduced compared with WT mice”

In Washc1 ΔHep mice with CETP expression, LDL-C levels are increased compared with WT mice.

“However, in Washc1 ΔHep , the LDL-C, HDL-C, as well as the apolipoproteins ApoB, Apo-AI, and ApoE levels were increased compared with WT mice (Figure 3, C and D).”

Hepatic Washc1 ablation does not affect VLDL production.

“We found that hepatic Washc1 ablation did not affect hepatic cholesterol and TG contents, VLDL production, and whole-body cholesterol synthesis rates (Supplemental Figure 3, A-D).”

WASHC1 deficiency destabilizes the WASH complex in liver.

“WASHC1 deficiency destabilizes the WASH complex and perturbs lysosomal structures in primary hepatocytes.”

Fecal neutral sterol and bile acid loss are unaffected in WASHC1-deficient mice.

“Importantly, fecal neutral sterol and bile acid loss were unaffected in WASHC1-deficient mice, indicating unaffected whole-body cholesterol turnover.”

Plasma decay of holoparticle HDL is not different between WT and Washc1 ΔHep mice.

“Plasma decay of radioiodine reflecting holoparticle HDL was not different between WT and Washc1 ΔHep mice (Figure 5C).”

Total protein levels of LDLR are reduced in WASH-deficient primary hepatocytes.

“In addition to the surface levels, the total protein levels of LDLR and LRP1 were also reduced in WASH-deficient primary hepatocytes (Figure 4, A and B).”

WASH deficiency induces lysosomal tubulation in hepatocytes.

“WASH deficiency induced lysosomal tubulation (Figure 1E).”

Hepatic WASHC1 deficiency results in increased plasma LDL-C and HDL-C in mice expressing CETP.

“Hepatic WASHC1 deficiency results in increased plasma LDL-C and HDL-C in mice expressing CETP.”

WASH deficiency does not affect the proteolysis of LDLR by PCSK9.

“WASH deficiency increases IDOL-mediated LDLR degradation but did not affect the proteolysis of LDLR by PCSK9.”

Loss of hepatic WASHC1 results in increased plasma LDL-C and HDL-C.

“Loss of hepatic WASHC1 results in increased plasma LDL-C and HDL-C.”

Hepatic uptake of HDL-C is impaired in hepatic WASH-deficient mice.

“Hepatic uptake of HDL-C is impaired by reduced surface levels of SR-BI in hepatic WASH-deficient mice.”

WASHC1 deficiency perturbs lysosomal structures in primary hepatocytes.

“WASHC1 deficiency destabilizes the WASH complex and perturbs lysosomal structures in primary hepatocytes.”

Cell-surface levels of SR-BI are reduced in hepatic WASH-deficient mice.

“Hepatic uptake of HDL-C is impaired by reduced surface levels of SR-BI in hepatic WASH-deficient mice.”

WASH deficiency increases IDOL-mediated LDLR degradation.

“WASH deficiency increases IDOL-mediated LDLR degradation but did not affect the proteolysis of LDLR by PCSK9.”

The hepatic WASH complex does not have a prominent role in the control of whole-body cholesterol turnover.

“These data indicate that the WASH complex in the liver plays an important role in the regulation of plasma LDL-C and HDL-C levels, but does not have a prominent role in the control of whole-body cholesterol turnover.”

Elevated plasma LDL cholesterol in Washc1 ΔHep mice is related to reduced hepatocytic surface levels of LDLR.

“Elevated plasma LDL cholesterol was related to reduced hepatocytic surface levels of the LDL receptor (LDLR) and the LDLR-related protein LRP1.”

WASH mediates endosomal recycling of LDLR back to the cell surface in MEFs.

“We have recently shown that WASH mediates endosomal recycling of LDLR back to the cell surface in MEFs (16).”

• cites [16] Bartuzi, 2016, CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL, Nat Commun sourceNot checked yet

Elevated plasma LDL cholesterol in Washc1 ΔHep mice is related to reduced hepatocytic surface levels of LRP1.

“Elevated plasma LDL cholesterol was related to reduced hepatocytic surface levels of the LDL receptor (LDLR) and the LDLR-related protein LRP1.”

HDL particles in Washc1 ΔHep mice are larger than in WT mice.

“Altogether, the shift of ApoA-I, ApoE, and HDL-C into earlier eluted FPLC fractions indicates that HDL particles in Washc1 ΔHep mice are larger than in WT mice (27)(28)(29).”

• cites (27)(28)(29)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The WASH complex participates in the sorting of ubiquitylated LDLR by IDOL to the lysosome.

“Altogether, these data imply that the WASH complex participates in the sorting of ubiquitylated LDLR by IDOL to the lysosome.”

WASH orchestrates the trafficking of LDLR, LRP1, and SR-BI to the plasma membrane for hepatic clearance of LDL-C and HDL-C.

“Our data indicate that WASH orchestrates the trafficking of the lipoprotein receptors LDLR and LRP1 as well as SR-BI to the plasma membrane for hepatic clearance of LDL-C and HDL-C, respectively.”

The WASH complex is a regulator of LDL as well as HDL metabolism.

“these findings identify the WASH complex as a regulator of LDL as well as HDL metabolism”

In vivo data support the notion that the WASH and CCC complexes act together to form a crucial sorting pathway required to maintain normal plasma cholesterol levels.

“These in vivo data support the notion that the WASH and CCC complexes act together to form a crucial sorting pathway that is required to maintain normal plasma cholesterol levels.”

This study extends the mechanistic basis for the increased plasma cholesterol levels in humans with defects in the WASH-CCC axis.

“this study extends the mechanistic basis for the increased plasma cholesterol levels in humans with defects in the WASH-CCC axis”

• AssumptionRests on an assumption: The function of the WASH complex in hepatic lipoprotein receptor trafficking is conserved between mice and humans.

LXR activation is decreased in Washc1 ΔHep mice.

“suggesting that LXR activation was decreased in Washc1 ΔHep mice.”

The disturbed endolysosomal architecture in Washc1 ΔHep mice does not cause defective intracellular cholesterol transport.

“Here, we found that the disturbed endolysosomal architecture in Washc1 ΔHep mice does not cause a defective intracellular cholesterol transport”

Hepatic WASH/LDLR deficiency mimics the plasma lipid phenotype in hepatic LRP1-deficient mice in an Ldlr-knockout background.

“Hepatic WASH/LDLR deficiency mimics the plasma lipid phenotype in hepatic LRP1-deficient mice in an Ldlr-knockout background (35)”

• cites [35] sourceNot checked — no full text of the source

Loss of hepatic WASHC1 may sensitize LRP1 for PCSK9-induced degradation.

“Remarkably, however, loss of hepatic WASHC1 may sensitize LRP1 for proprotein convertase subtilisin/kexin type 9-induced degradation.”

Current and previous mouse models mimic the dyslipidemic phenotype of patients with RSS and X-linked intellectual disability.

“Our current and previous mouse models mimic the dyslipidemic phenotype of patients with RSS and those with X-linked intellectual disability”

The WASH and CCC complexes act in concert in the endosomal cargo recycling pathway.

“Here, we provide genetic evidence that the WASH and CCC complexes act in concert in the endosomal cargo recycling pathway”

The WASH complex is required for hepatic LRP1-mediated cholesterol uptake in vivo.

“suggesting that the WASH complex is also required for hepatic LRP1-mediated cholesterol uptake in vivo.”

It is unlikely that hepatic lipase contributes to the increased plasma HDL-C levels in hepatic WASH-deficient mice.

“which makes it unlikely that HL contributes to the increased plasma HDL-C levels in hepatic WASH-deficient mice.”

The WASH complex has a pivotal role in the maintenance of plasma cholesterol levels.

“Here, we report that the WASH complex also has a pivotal role in the maintenance of plasma cholesterol levels.”

The WASH complex provides in vivo evidence for endosomal trafficking of SR-BI in hepatocytes.

“provide in vivo evidence for endosomal trafficking of scavenger receptor class B type I in hepatocytes.”

The WASH and CCC complexes act in concert to regulate plasma lipid levels.

“Results from previous and current studies imply that the WASH and CCC complex act in concert to regulate plasma lipid levels.”

The WASH complex is essential for the architecture of the endolysosomal system in hepatocytes.

“we show that the WASH complex is also essential for the architecture of the endolysosomal system in hepatocytes”

The localization of SR-BI at the plasma membrane largely relies on the WASH-CCC axis.

“Our results indicate that the localization of SR-BI at the plasma membrane largely relies on the WASH-CCC axis.”

The impaired hepatic HDL-C uptake in hepatic WASH-deficient mice is caused by reduced surface levels of SR-BI.

“Hepatic uptake of HDL-C is impaired by reduced surface levels of SR-BI in hepatic WASH-deficient mice.”