Cholesterol: from feeding to gene regulation.
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ABSTRACT:
SUBMITTER: Martini C
PROVIDER: S-EPMC2474947 | biostudies-other | 2007 Nov
REPOSITORIES: biostudies-other
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Project description:Metabolic-associated steatohepatitis is a progressive fatty liver disease caused, in part, by hepatocyte stress linked to cholesterol overload. Counteracting this stress may be beneficial but there is insufficient understanding of underlying stress defenses to develop a therapeutic strategy. Here, we aimed to elucidate how stress-adaptive transcription factors, nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2), counteract hepatic cholesterol overload and determine whether they function cooperatively. C57bl/6 mice were fed high fat, fructose, and cholesterol diet (HFFC). Expression profiling and phenotypic analyses were done on liver of mice with adult-onset and hepatocyte-specific deficiency of NRF1, NRF2, or both, and results compared to control. Chromatin immunoprecipitation (ChIP) sequencing was done and combined with expression profiles to identify genes that NRF1 and NRF2 interact with and regulate in vivo. Three weeks HFFC diet feeding to mice with NRF1 and NRF2 deficiency caused severe steatohepatitis and increased hepatic cholesterol storage. These outcomes did not occur in single gene-deficient mice or control. Expression profiling at a time preceding hepatic cholesterol overload and ChIP sequencing profiling revealed complementary gene regulation by NRF1 and NRF2 to promote cholesterol excretion and mitigate hazardous metabolic biproducts generated from converting cholesterol to bile acid. Consequently, combined gene deficiency, and not single-gene deficiency, increased liver oxidized protein level, decreased cholesterol in bile, and increased unconjugated bile acid in liver and bile. We discover, for the first time, that NRF1 and NRF2 work together to protect liver against damaging effects of excess cholesterol. Targeting these combined actions may prove an effective therapeutic strategy
2023-03-22 | PXD032069 | Pride
Project description:Prostacyclin and its prostacyclin receptor, the I Prostanoid (IP), play essential roles in regulating hemostasis and vascular tone and have been implicated in a range cardio-protective effects but through largely unknown mechanisms. In this study, the influence of cholesterol on human IP [(h)IP] gene expression was investigated in cultured vascular endothelial and platelet-progenitor megakaryocytic cells. Cholesterol depletion increased human prostacyclin receptor (hIP) mRNA, hIP promoter-directed reporter gene expression, and hIP-induced cAMP generation in all cell types. Furthermore, the constitutively active sterol-response element binding protein (SREBP)1a, but not SREBP2, increased hIP mRNA and promoter-directed gene expression, and deletional and mutational analysis uncovered an evolutionary conserved sterol-response element (SRE), adjacent to a known functional Sp1 element, within the core hIP promoter. Moreover, chromatin immunoprecipitation assays confirmed direct cholesterol-regulated binding of SREBP1a to this hIP promoter region in vivo, and immunofluorescence microscopy corroborated that cholesterol depletion significantly increases hIP expression levels. In conclusion, the hIP gene is directly regulated by cholesterol depletion, which occurs through binding of SREBP1a to a functional SRE within its core promoter. Mechanistically, these data establish that cholesterol can regulate hIP expression, which may, at least in part, account for the combined cardio-protective actions of low serum cholesterol through its regulation of IP expression within the human vasculature.
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Project description:The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. Consequently, patients with this disease have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. We previously mapped the STSL locus to human chromosome 2p21 and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patients.
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Project description:In the past decade, microRNAs (miRNAs) have emerged as key regulators of circulating levels of lipoproteins. Specifically, recent work has uncovered the role of miRNAs in controlling the levels of atherogenic low-density lipoprotein LDL (LDL)-cholesterol by post-transcriptionally regulating genes involved in very low-density lipoprotein (VLDL) secretion, cholesterol biosynthesis, and hepatic LDL receptor (LDLR) expression. Interestingly, several of these miRNAs are located in genomic loci associated with abnormal levels of circulating lipids in humans. These findings reinforce the interest of targeting this subset of non-coding RNAs as potential therapeutic avenues for regulating plasma cholesterol and triglyceride (TAG) levels. In this review, we will discuss how these new miRNAs represent potential pre-disposition factors for cardiovascular disease (CVD), and putative therapeutic targets in patients with cardiometabolic disorders. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
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Project description:1. Labelled thoracic-duct lymph was collected from rats and rabbits after test meals containing [(14)C]cholesterol and [2-(3)H]glyceryl trioleate. 2. The metabolism of labelled cholesterol and triglyceride was studied in normally fed and cholesterol-fed rats and rabbits injected with radioactive lymph from the same species. 3. In normally fed animals of both species, 10min after intravenous administration, about 80% of lymph cholesteryl ester but only about 10% of triglyceride was recovered in the liver after clearance from the plasma. This distribution is consistent with participation of ;remnant' particles in the metabolism of dietary lymph particles. 4. The metabolism of cleared lymph lipoprotein constituents was unchanged in cholesterol-fed rats, but the recovery of cholesteryl ester in the livers of the cholesterol-fed rabbits was decreased to 30% of the cleared dose. 5. The low recovery in cholesterol-fed rabbits was accounted for mainly by increased hydrolysis of cholesteryl ester. 6. It is proposed that differences between rats and rabbits in metabolism of dietary cholesterol might be partly due to the observed enhancement of hydrolysis of lymph lipoprotein cholesteryl ester in rabbits.
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Project description:BackgroundPhytosterol supplementation of 2 g/d is recommended by the National Cholesterol Education Program to reduce LDL cholesterol. However, the effects of different intakes of phytosterol on cholesterol metabolism are uncertain.ObjectiveWe evaluated the effects of 3 phytosterol intakes on whole-body cholesterol metabolism.DesignIn this placebo-controlled, crossover feeding trial, 18 adults received a phytosterol-deficient diet (50 mg phytosterols/2000 kcal) plus beverages supplemented with 0, 400, or 2000 mg phytosterols/d for 4 wk each, in random order. All meals were prepared in a metabolic kitchen; breakfast and dinner on weekdays were eaten on site. Primary outcomes were fecal cholesterol excretion and intestinal cholesterol absorption measured with stable-isotope tracers and serum lipoprotein concentrations.ResultsPhytosterol intakes (diet plus supplements) averaged 59, 459, and 2059 mg/d during the 3 diet periods. Relative to the 59-mg diet, the 459- and 2059-mg phytosterol intakes significantly (P < 0.01) increased total fecal cholesterol excretion (36 +/- 6% and 74 +/- 10%, respectively) and biliary cholesterol excretion (38 +/- 7% and 77 +/- 12%, respectively) and reduced percentage intestinal cholesterol absorption (-10 +/- 1% and -25 +/- 3%, respectively). Serum LDL cholesterol declined significantly only with the highest phytosterol dose (-8.9 +/- 2.3%); a trend was observed with the 459-mg/d dose (-5.0 +/- 2.1%; P = 0.077).ConclusionsDietary phytosterols in moderate and high doses favorably alter whole-body cholesterol metabolism in a dose-dependent manner. A moderate phytosterol intake (459 mg/d) can be obtained in a healthy diet without supplementation. This trial was registered at clinicaltrials.gov as NCT00860054.
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Project description:The liver maintains metabolic homeostasis by integrating the regulation of nutrient status with both hormonal and neural signals. Many studies on hepatic signaling in response to nutrients have been conducted in mice. However, no in-depth study is currently available that has investigated genome-wide changes in gene expression during the normal physiological fasting-feeding cycle in nutrient-sensitive and -insensitive mice. Using two strains of mice, C57BL/6J and BALB/cJ, and deploying deep RNA-Seq complemented with quantitative RT-PCR, we found that feeding causes substantial and transient changes in gene expression in the livers of both mouse strains. The majority of significantly changed transcripts fell within the areas of biological regulation and cellular and metabolic processes. Among the metabolisms of three major types of macronutrients (i.e. carbohydrates, proteins, and lipids), feeding affected lipid metabolism the most. We also noted that the C57BL/6J and BALB/cJ mice significantly differed in gene expression and in changes in gene expression in response to feeding. In both fasted and fed states, both mouse strains shared common expression patterns for about 10,200 genes, and an additional 400-600 genes were differentially regulated in one strain but not the other. Among the shared genes, more lipogenic genes were induced upon feeding in BABL/cJ than in C57BL/6J mice. In contrast, in the population of differentially enriched genes, C57BL/6J mice expressed more genes involved in lipid metabolism than BALB/cJ mice. In summary, these results reveal that the two mouse strains used here exhibit several differences in feeding-induced hepatic responses in gene expression, especially in lipogenic genes.
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Project description:The ability of cells to precisely control gene expression in response to intracellular and extracellular signals plays an important role in both normal physiology and in pathological settings. For instance, the accumulation of excess cholesterol by macrophages initiates a genetic response mediated by the liver X receptors (LXRs)-? (NR1H3) and LXR? (NR1H2), which facilitates the transport of cholesterol out of cells to high-density lipoprotein particles. Studies using synthetic LXR agonists have also demonstrated that macrophage LXR activation simultaneously induces a second network of genes that promotes fatty acid and triglyceride synthesis that may support the detoxification of excess free cholesterol by storage in the ester form. We now show that treatment of human THP-1 macrophages with endogenous or synthetic LXR ligands stimulates both transcriptional and posttranscriptional pathways that result in the selective recruitment of the LXR? subtype to LXR-regulated promoters. Interestingly, when human or mouse macrophages are loaded with cholesterol under conditions that mimic the development of atherogenic macrophage foam cells, a selective LXR response is generated that induces genes mediating cholesterol transport but does not coordinately regulate genes involved in fatty acid synthesis. The gene-selective response to cholesterol loading occurs, even in the presence of LXR? binding to the promoter of the gene encoding the sterol regulatory element-binding protein-1c, the master transcriptional regulator of fatty acid synthesis. The ability of promoter bound LXR? to recruit RNA polymerase to the sterol regulatory element-binding protein-1c promoter, however, appears to be ligand selective.
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