Cholesterol Precursors Lathosterol Research Articles

Protective role of plant sterol and stanol esters in liver inflammation: insights from mice and humans.

The inflammatory component of non–alcoholic steatohepatitis (NASH) can lead to irreversible liver damage. Therefore there is an urgent need to identify novel interventions to combat hepatic inflammation. In mice, omitting cholesterol from the diet reduced hepatic inflammation. Considering the effects of plant sterol/stanol esters on cholesterol metabolism, we hypothesized that plant sterol/stanol esters reduces hepatic inflammation. Indeed, adding plant sterol/stanol esters to a high-fat-diet reduced hepatic inflammation as indicated by immunohistochemical stainings and gene expression for inflammatory markers. Finally, adding sterol/stanol esters lowered hepatic concentrations of cholesterol precursors lathosterol and desmosterol in mice, which were highly elevated in the HFD group similarly as observed in severely obese patients with NASH. In vitro, in isolated LPS stimulated bone marrow derived macrophages desmosterol activated cholesterol efflux whereas sitostanol reduced inflammation. This highly interesting observation that plant sterol/stanol ester consumption leads to complete inhibition of HFD-induced liver inflammation opens new venues in the treatment and prevention of hepatic inflammation.

Relationship Between Cholesterol Metabolism, Apoe and Brain Volumes In Alzheimer‘s Disease

APOE genotype, aging and midlife hypercholesterolemia are well-established risk factors for late-onset Alzheimer’s disease (AD). ApoE and cholesterol are involved in the pathogenesis of AD since they influence amyloid-β accumulation and Tau pathology. APOE ε4 carriers were found to present lower levels of amyloid-β1–42, higher tau and phosphorylated tau and a higher degree of brain atrophy at any disease stage. Presence of ApoE4 shifts the onset of the disease towards a younger age and makes progression faster. Hypercholesterolemia together with other major cardiovascular risk factors were found to be involved in the pathogenesis of AD, but reduced plasma cholesterol levels were described in demented patients. Significant correlations were found between cholesterol precursors lathosterol, lanosterol and 24S-hydroxycholesterol (a putative marker of brain cholesterol turnover) in plasma and brain atrophy as quantified by MRI. It is likely that neurodegeneration affects both brain and whole-body cholesterol metabolism in AD.

H03 Cerebral and extracerebral cholesterol biosynthesis is impaired in Huntington's disease patients

BackgroundCholesterol in the CNS is fundamental for membrane trafficking, signal transduction and synaptogenesis and almost all the brain cholesterol is synthetised locally. Homeostasis is maintained through a neuronal specific cholesterol...

Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (beta = 0.020, P = 0.587 for campesterol/TC and beta<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations.

Cholesterol 25-Hydroxylase on Chromosome 10q Is a Susceptibility Gene for Sporadic Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia. It is characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5′ region of CH25H revealed three common haplotypes, CH25Hχ2, CH25Hχ3 and CH25Hχ4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hχ4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain Aβ deposits in carriers of CH25Hχ4 and CH25Hχ3 haplotypes, whereas no Aβ deposits were present in CH25Hχ2 carriers. Together, these results are compatible with a role of CH25Hχ4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain Aβ deposition.

Ratio of lathosterol to campesterol in serum predicts the cholesterol-lowering effect of sitostanol-supplemented margarine

Plant sterol/stanol margarines are recommended as a lipid-lowering dietary supplement in the treatment of hypercholesterolemia. Parameters predicting the individual cholesterol-lowering effect have not been elucidated so far. Therefore, we investigated the responsiveness to sitostanol-supplemented margarine in a specially selected population. From a total number of 137 male subjects with hypercholesterolemia, eight subjects with the lowest and eight subjects with the highest ratios of lathosterol to campesterol in serum were included in the study. They received 1 g sitostanol-supplemented margarine b.i.d. for four weeks. Serum lipoproteins, the cholesterol precursor lathosterol, the plant sterols campesterol and sitosterol were measured. Subjects with a low ratio of lathosterol to campesterol had a significant decrease of serum total cholesterol (-14.2%; p < 0.01) and LDL cholesterol (-13.8%; p < 0.01; responder). In subjects with a high ratio there was no significant change in total cholesterol and LDL cholesterol (2.2 and 4.3%; non-responder). The ratio of serum lathosterol to campesterol predicts the reduction of total cholesterol and LDL cholesterol during administration of sitostanol-supplemented margarine in patients with mild hypercholesterolemia.

High doses of simvastatin, pravastatin, and cholesterol reduce brain cholesterol synthesis in guinea pigs

Recent epidemiological studies suggest that inhibitors of 3-hydroxy-3-methyl-glutaryl CoA reductase, so-called statins, are effective in lowering the prevalence of Alzheimer’s disease. Whether the effect of statins is due to a local inhibition of cholesterol synthesis in the brain or whether it is mediated by the reduced levels of cholesterol in the circulation is not known. In the present work, we tested the possibility that high doses of lipophilic and hydrophilic statins, simvastatin and pravastatin, respectively, or a diet high in cholesterol could affect cholesterol homeostasis in the brain of guinea pigs. The total brain cholesterol levels were not affected by high-dose simvastatin or pravastatin treatment. Significantly lower levels of the cholesterol precursor lathosterol and its ratio to cholesterol were found in the brains of simvastatin and pravastatin-treated animals. 24S-Hydroxycholesterol, the transportable form of cholesterol across the blood–brain barrier, was significantly lower in the brain of pravastatin-treated animals. Excessive cholesterol feeding resulted in higher serum cholesterol levels but did not affect total brain cholesterol level. However, de novo cholesterol synthesis in the brain seemed to be down-regulated, as indicated by lower absolute levels and cholesterol-related ratios of lathosterol compared with controls. The passage of deuterium-labeled cholesterol across the blood–brain barrier in one animal was found to be approximately 1%. Our results suggest that brain cholesterol synthesis in guinea pigs can be slightly, but significantly, influenced by high doses of lipophilic and hydrophilic statins as well as by high dietary cholesterol intake, while total brain cholesterol content and thus, cholesterol homeostasis is maintained.

Determination of changes in serum lathosterol during treatment with simvastatin to evaluate the role of lathosterol as a parameter for whole body cholesterol synthesis

Serum levels of cholesterol and the cholesterol precursor lathosterol were determined in five healthy volunteers who took 20 mg simvastatin daily during 1 week. During this period and for the following 5 days blood samples were collected. Five days after ingestion of simvastatin, serum lathosterol had already reached a steady-state level and its concentration decreased by 55–73%. In contrast, the cholesterol concentration decreased only by 17–29% and did not reach a steady-state level even after 7 days of treatment. After withdrawal of simvastatin, serum lathosterol quickly rose to pretreatment values. From the data a mean half-life of lathosterol could be calculated of 23.5 ± 6.6 h during treatment with simvastatin and of 28.7 ± 15.13 h after its withdrawal, taking, respectively, the decrease and increase of serum lathosterol into account. From these data it can be concluded that serum lathosterol is also a good parameter for determining whole body cholesterol synthesis during non-steady-state conditions, although plasma mevalonic acid, another (early) cholesterol precursor, is preferred owing to its much shorter reported half-life.

Apolipoprotein E phenotype and cholesterol metabolism in familial hypercholesterolemia

Serum lipids, lipoproteins, cholesterol absorption and parameters of cholesterol metabolism were related to apolipoprotein E phenotypes in 38 patients with familial xanthomatous hypercholesterolemia. Serum lipids and lipoproteins were similar in 2 most frequent apo E phenotypes E 3 3 and E 4 3 . Coronary artery disease was not related to the apo E phenotypes. Cholesterol absorption efficiency was significantly lower in the apo E 3 3 patients than in the apo E 4 3 group. A high serum level of cholesterol precursor lathosterol, a high lathosterol/ sitosterol ratio and sterol balance data suggest that cholesterol synthesis may be slightly higher in the apo E 3 3 than E 4 3 group. The findings indicate that the genetically determined apo E polymorphism contributes to cholesterol absorption efficiency in FH patients, but serum total and lipoprotein cholesterol levels are poorly related to apo E isoforms.

Effects of proximate cholesterol precursors and steroid hormones on mouse myeloma growth in serum-free medium.

The proximate cholesterol precursors lathosterol, 7-dehydrocholesterol and desmosterol supported the growth of NS-1 and X63 mouse myeloma cells. These cells and X63.653 cells are cholesterol auxotrophs, yet each was able to convert [3H]lathosterol to [3H]cholesterol. These results are consistent with the conclusion that cholesterol auxotrophy in these myeloma cells is due to a deficiency in 3-ketosteroid reductase activity. The steroid hormones testosterone, progesterone and hydrocortisone could not replace cholesterol as a medium supplement. These results provide a greater understanding of the cholesterol auxotrophy characteristic of cell lines clonally-derived from the MOPC 21 myeloma tumor, and they provide a rational basis for the use of sterols in defined culture medium for mouse myeloma cells.