Recent evidence, including massive gene-expression analysis and a wide-variety of other multi-omics approaches, demonstrates an interplay between gut microbiota and the regulation of plasma lipids. Gut microbial metabolism of choline and l-carnitine results in the formation of trimethylamine (TMA) and concomitant conversion into trimethylamine-N-oxide (TMAO) by liver flavin monooxygenase 3 (FMO3). The plasma level of TMAO is determined by the genetic variation, diet and composition of gut microbiota. Multiple studies have demonstrated an association between TMAO plasma levels and the risk of atherothrombotic cardiovascular disease (CVD). We aimed to review the molecular pathways by which TMAO production and FMO3 exert their proatherogenic effects. TMAO may promote foam cell formation by upregulating macrophage scavenger receptors, deregulating enterohepatic cholesterol and bile acid metabolism and impairing macrophage reverse cholesterol transport (RCT). Furthermore, FMO3 may promote dyslipidemia by regulating multiple genes involved in hepatic lipogenesis and gluconeogenesis. FMO3 also impairs multiple aspects of cholesterol homeostasis, including transintestinal cholesterol export and macrophage-specific RCT. At least part of these FMO3-mediated effects on lipid metabolism and atherogenesis seem to be independent of the TMA/TMAO formation. Overall, these findings have the potential to open a new era for the therapeutic manipulation of the gut microbiota to improve CVD risk.

Breast cancer is the most prevalent cancer and primary cause of cancer-related mortality in women. The identification of risk factors can improve prevention of cancer, and obesity and hypercholesterolemia represent potentially modifiable breast cancer risk factors. In the present work, we review the progress to date in research on the potential role of the main cholesterol transporters, low-density and high-density lipoproteins (LDL and HDL), on breast cancer development. Although some studies have failed to find associations between lipoproteins and breast cancer, some large clinical studies have demonstrated a direct association between LDL cholesterol levels and breast cancer risk and an inverse association between HDL cholesterol and breast cancer risk. Research in breast cancer cells and experimental mouse models of breast cancer have demonstrated an important role for cholesterol and its transporters in breast cancer development. Instead of cholesterol, the cholesterol metabolite 27-hydroxycholesterol induces the proliferation of estrogen receptor-positive breast cancer cells and facilitates metastasis. Oxidative modification of the lipoproteins and HDL glycation activate different inflammation-related pathways, thereby enhancing cell proliferation and migration and inhibiting apoptosis. Cholesterol-lowering drugs and apolipoprotein A-I mimetics have emerged as potential therapeutic agents to prevent the deleterious effects of high cholesterol in breast cancer.

Sitosterolemia is a rare autosomal recessively inherited disease caused by mutations affecting ABCG5 or ABCG8, which are located on human chromosome band 2p21. Around 100 cases have been reported in the literature. Sitosterolemic patients typically exhibit a 30-fold to 100-fold increase in plasma concentrations of plant sterols. The clinical manifestations include xanthomas, premature atherosclerosis, hemolytic anemia, and macrothrombocytopenia. It is noteworthy that abnormal hematological parameters may be the only clinical feature of sitosterolemic patients, suggesting that sitosterolemia may be more frequent than previously thought. Severe accumulation of plant sterols in mouse models of sitosterolemia induced complex cardiac lesions, anemia, and macrothrombocytopenia, disrupted adrenal and liver cholesterol homeostasis, and caused infertility and hypertriglyceridemia. It remains unclear whether all disease traits are present in sitosterolemic patients. The drug ezetimibe appears to be effective in reducing plasma plant sterol levels, promotes xanthoma regression, and improves the cardiovascular and hematological signs in sitosterolemic patients.

Background Women with polycystic ovarian syndrome have a high prevalence of metabolic syndrome and type 2 diabetes mellitus. Blacks and Hispanics have a high morbidity and mortality due to cardiovascular disease and diabetes mellitus in the general population. Since metabolic syndrome is a risk factor for development of type 2 diabetes and cardiovascular disease, understanding any racial and ethnic differences in metabolic syndrome amongst women with polycystic ovarian syndrome is important for prevention strategies. However, data regarding racial/ethnic differences in metabolic phenotype amongst women with polycystic ovary syndrome is inconsistent. Objective To determine if there are racial/ethnic differences in insulin resistance, metabolic syndrome and hyperandrogenemia in women with polycystic ovarian syndrome. Study Design Secondary data analysis of a prospective multicenter, double blind controlled clinical trial, the Pregnancy in Polycystic Ovary Syndrome II study, conducted in 11 academic health centers. Data on 702 women with polycystic ovarian syndrome aged 18-40 years who met modified Rotterdam criteria for the syndrome and wished to conceive were included in the study. Women were grouped into racial/ethnic categories Non-Hispanic Whites, non-Hispanic Blacks and Hispanic. The main outcomes were the prevalence of insulin resistance, metabolic syndrome and hyperandrogenemia in the different racial/ethnic groups. Results BMI (35.1 ± 9.8 vs. 35.7 ± 7.9 vs. 36.4 ± 7.9 kg/m2) and waist circumference (106.5 ± 21.6 vs. 104.9 ± 16.4 vs. 108.7 ± 7.3 cm) did not differ significantly between non-Hispanic White, non-Hispanic Black and Hispanic women. Hispanic women with PCOS had a significantly higher prevalence of hirsutism (93.8 vs. 86.8%), abnormal free androgen index (FAI) (75.8 vs. 56.5%), abnormal homeostasis model assessment (HOMA) (52.3 vs. 38.4%) and hyperglycemia (14.8 vs. 6.5%), as well as lower sex hormone binding globulin compared to non-Hispanic Whites. Non-Hispanic Black women had a significantly lower prevalence of metabolic syndrome (24.5 vs. 42.2%) compared with Hispanic women, and lower serum triglyceride levels compared to both Hispanics and non-Hispanic Whites (85.7 ± 37.3 vs. 130.2 ± 57.0 vs. 120.1 ± 60.5 vs. mg/dL, p<0.01), with a markedly lower prevalence of hypertriglyceridemia (5.1 vs. 28.3 vs. 30.5%, p<0.01) compared to the other two groups. Comment Hispanic women with PCOS have the most severe phenotype, both in terms of hyperandrogenism and metabolic criteria. Non-Hispanic Black women have an overall milder polycystic ovarian syndrome phenotype than Hispanics and in some respects, than Non-Hispanic White women.

ObjectiveThe very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)β/δ and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation.MethodsStudies were conducted in wild-type and Pparβ/δ-null mice, primary mouse hepatocytes, human Huh-7 hepatocytes, and liver biopsies from control subjects and patients with moderate and severe hepatic steatosis.ResultsIncreased VLDLR levels were observed in liver of Pparβ/δ-null mice and in Pparβ/δ-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. Moreover, by using a neutralizing antibody against FGF21, Fgf21-null mice and by treating mice with recombinant FGF21, we show that FGF21 may protect against hepatic steatosis by attenuating endoplasmic reticulum (ER) stress-induced VLDLR upregulation. Finally, in liver biopsies from patients with moderate and severe hepatic steatosis, we observed an increase in VLDLR levels that was accompanied by a reduction in PPARβ/δ mRNA abundance and DNA-binding activity compared with control subjects.ConclusionsOverall, these findings provide new mechanisms by which PPARβ/δ and FGF21 regulate VLDLR levels and influence hepatic steatosis development.

Rationale: The HDL-mediated stimulation of cellular cholesterol efflux initiates the reverse cholesterol pathway from macrophages (m-RCT), which ends in the fecal excretion of macrophage-derived unesterified cholesterol (UC). Early studies established that LDL particles could act as efficient intermediate acceptors of cellular-derived UC, thereby preventing the saturation of HDL particles and facilitating their cholesterol efflux capacity (CEC). However, the capacity of LDL to act as a plasma cholesterol reservoir and its potential impact in supporting the m-RCT pathway in vivo both remain unknown. Objective: We investigated LDL contributions to the m-RCT pathway in hypercholesterolemic mice. Methods and Results: Macrophage cholesterol efflux induced either in vitro by LDL added to the culture media either alone or together with HDL, or ex vivo by plasma derived from subjects with familial hypercholesterolemia (FH), was assessed. In vivo, m-RCT was evaluated in mouse models of hypercholesterolemia that were naturally deficient in CETP and fed a Western-type diet. LDL induced the efflux of radiolabeled UC from cultured macrophages, and, in the simultaneous presence of HDL, a rapid transfer of the radiolabeled UC from HDL to LDL occurred. However, LDL did not exert a synergistic effect on HDL CEC in the FH plasma. The m-RCT rates of the LDL receptor (LDLr)-KO, LDLr-KO/APOB100, and PCSK9-overexpressing mice were all significantly reduced relative to the wild-type mice. In contrast, m-RCT remained unchanged in human APOB100 transgenic mice with fully functional LDLr, despite increased levels of plasma APOB-containing lipoproteins. Conclusions: Hepatic LDLr plays a critical role in the flow of macrophage-derived UC to feces, while the plasma increase of APOB-containing lipoproteins is unable to stimulate m-RCT. The results indicate that, besides the major HDL-dependent m-RCT pathway via SR-BI to the liver, a CETP-independent m-RCT path exists, in which LDL mediates the transfer of cholesterol from macrophages to feces.

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