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Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine.

ABSTRACT: Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid constituent of the inner layer of the plasma membrane (PM). In PTDSS1-deficient cells where PS is low, LDL cholesterol leaves lysosomes but fails to reach the ER, instead accumulating in the PM. The addition of PS restores cholesterol transport to the ER. We conclude that LDL cholesterol normally moves from lysosomes to the PM. When the PM cholesterol exceeds a threshold, excess cholesterol moves to the ER in a process requiring PS. In the ER, excess cholesterol acts to reduce cholesterol uptake, preventing toxic cholesterol accumulation. These studies reveal that one lipid-PS-controls the movement of another lipid-cholesterol-between cell membranes. We relate these findings to recent evidence indicating that PM-to-ER cholesterol transport is mediated by GRAMD1/Aster proteins that bind PS and cholesterol.

SUBMITTER: Trinh MN

PROVIDER: S-EPMC7414171 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine.

Trinh Michael N MN Brown Michael S MS Goldstein Joseph L JL Han Jaeil J Vale Gonçalo G McDonald Jeffrey G JG Seemann Joachim J Mendell Joshua T JT Lu Feiran F

Proceedings of the National Academy of Sciences of the United States of America 20200720 31

Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid ...[more]

PMID: 32690708

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Project description:BackgroundPhenylketonuria (PKU; OMIM#261600) is a rare metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene resulting in high phenylalanine (Phe) in blood and brain. If not treated early this results in intellectual disability, behavioral and psychiatric problems, microcephaly, motor deficits, eczematous rash, autism, seizures, and developmental problems. There is a controversial discussion of whether patients with PKU have an additional risk for atherosclerosis due to interference of Phe with cholesterol synthesis and LDL-cholesterol regulation. Since cholesterol also plays a role in membrane structure and myelination, better insight into the clinical significance of the impact of Phe on lipoprotein metabolism is desirable. In 22 treated PKU patients (mean age 38.7 years) and 14 healthy controls (mean age 35.2 years), we investigated plasma with NMR spectroscopy and quantified 105 lipoprotein parameters (including lipoprotein subclasses) and 24 low molecular weight parameters. Analysis was performed on a 600 MHz Bruker AVANCE IVDr spectrometer as previously described.ResultsConcurrent plasma Phe in PKU patients showed a wide range with a mean of 899 μmol/L (50-1318 μmol/L). Total cholesterol and LDL-cholesterol were significantly lower in PKU patients versus controls: 179.4 versus 200.9 mg/dL (p < 0.02) and 79.5 versus 104.1 mg/dL (p < 0.0038), respectively. PKU patients also had lower levels of 22 LDL subclasses with the greatest differences in LDL2 Apo-B, LDL2 Particle Number, LDL2-phospholipids, and LDL2-cholesterol (p < 0.0001). There was a slight negative correlation of total cholesterol and LDL-cholesterol with concurrent Phe level. VLDL5-free cholesterol, VLDL5-cholesterol, VLDL5-phospholipids, and VLDL4-free cholesterol showed a significant (p < 0.05) negative correlation with concurrent Phe level. There was no difference in HDL and their subclasses between PKU patients and controls. Tyrosine, glutamine, and creatinine were significantly lower in PKU patients compared to controls, while citric and glutamic acids were significantly higher.ConclusionsUsing NMR spectroscopy, a unique lipoprotein profile in PKU patients can be demonstrated which mimics a non-atherogenic profile as seen in patients treated by statins.

Project description:BackgroundA couple of studies indicate a favorable impact of lupin protein on cardiovascular risk factors in humans. These studies, however, used relatively high doses of > 33 g/d, which can hardly be consumed under physiological conditions. Therefore, we investigated the effect of 25 g/d lupin protein isolate (LPI) on selected cardiovascular markers and on serum amino acids.MethodsA total of 33 hypercholesterolemic subjects participated in a randomized, controlled, double-blind crossover study. LPI and the active comparator milk protein isolate (MPI) were incorporated in protein drinks and consumed over 8 wk separated by a 4 wk washout period. Anthropometric data, blood pressure, and nutrient intake were assessed at baseline and after 8 wk of both protein interventions. Blood was sampled at baseline, wk 4 and wk 8. All 33 subjects were included in final statistical analyses using repeated measures ANOVA with the general linear model or using linear mixed model.ResultsExcept for higher HDL cholesterol at wk 4 of LPI (P ≤ 0.036), anthropometric parameters, blood pressure, and plasma lipids did not differ among LPI and MPI intervention. Compared to baseline, the primary outcome LDL cholesterol was significantly reduced after 4 wk of both interventions (P ≤ 0.008), while LDL:HDL cholesterol ratio was decreased only by LPI (P = 0.003). These time effects were restricted to subjects with higher hypercholesterolemia and disappeared after 8 wk. Blood pressure was reduced after 8 wk of LPI (P ≤ 0.044). Almost all serum amino acids were higher at wk 4 but not at wk 8 of MPI compared to LPI. Following 4 wk and 8 wk of LPI intervention, most amino acids remained unchanged. Both interventions caused a slight, but significant rise in body weight and body fat after 8 wk (P ≤ 0.045).ConclusionIn conclusion, 25 g LPI can beneficially modulate plasma LDL cholesterol at least over short-term. Using appropriate dietetic conditions that improve consumer compliance and avoid changes in energy intake as well as in body composition, lupin protein could positively impact cardiovascular risk factors particularly in individuals with higher hypercholesterolemia.Trial registrationClinicalTrials.gov: NCT01304992.

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Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine.

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Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine.

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