Bibliographic record
Abstract
Plasma low‐density lipoprotein cholesterol (LDL‐C) levels are positively correlated with risk of cardiovascular disease. LDL is produced from catabolism of very low‐density lipoprotein (VLDL) that is exclusively secreted from hepatocytes. Inhibition of VLDL secretion reduces plasma LDL‐C levels. LDL is cleared from circulation via hepatic LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is mainly secreted from the liver and promotes LDLR degradation, increasing plasma LDL‐C levels. Understanding mechanisms of VLDL and PCSK9 secretion are crucial for identifying novel therapeutic targets. Surfeit 4 (Surf4) is a cargo receptor that resides in the endoplasmic reticulum (ER). Here, we investigated its role in VLDL and PCSK9 secretion. We generated Surf4 liver specific knockout ( Surf4 LKO ) mice and found that knockout of Surf4 did not affect PCSK9 secretion but significantly reduced plasma levels of cholesterol, triglyceride, and apolipoprotein B (apoB). In cultured human hepatocytes, Surf4 co‐immunoprecipitated and co‐localized with apoB100, and Surf4 silencing reduced secretion of apoB100. VLDL secretion was impaired in Surf4 LKO mice, causing the retention of small lipid particles in the hepatic ER lumen. However, liver lipid levels and plasma alanine aminotransferase activity were comparable in Surf4 LKO and Surf4 FLOX mice. Furthermore, knockdown of Surf4 in LDLR knockout ( Ldlr ‐/‐ ) mice significantly reduced triglyceride secretion and plasma levels of apoB and non‐HDL cholesterol but had no effect on plasma HDL cholesterol or apoA‐I levels. Surf4 silencing markedly reduced the development of atherosclerosis without causing notable liver damage. Expression of stearoyl‐CoA‐1 (SCD1) was reduced in the liver of Surf4 LKO mice and Surf4 knockdown Ldlr ‐/‐ mice. In summary, Surf4 is not required for PCSK9 secretion, instead it interacts with apoB100 and facilitates VLDL secretion. Hepatic deficiency of Surf4 reduces VLDL secretion and the development of atherosclerosis but does not cause hepatic lipid accumulation or liver damage. Thus, hepatic Surf4 can be a novel therapeutic target to reduce LDL production and the risk of cardiovascular disease. Translational perspective. Patients with homozygous familial hypercholesterolemia harboring LDLR null mutations or with autosomal recessive hypercholesterolemia cannot be effectively treated by currently lipid‐lowering drugs, statins and PCSK9 inhibitors. Inhibition of VLDL secretion can markedly reduce plasma levels of cholesterol and the development of atherosclerosis. Our findings that Surf4 facilitated VLDL secretion, and inhibition of Surf4 drastically reduced plasma cholesterol levels and the development of atherosclerosis without causing notable liver damage provide critical information for the development of novel LDL production‐based therapies through inhibiting hepatic Surf4.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".