Hepatic Cholesterol Synthesis Research Articles

Degree of serum LDL cholesterol reduction by simvastatin and ezetimibe is dependent on baseline LDL cholesterol concentration but not on baseline values and changes in cholesterol synthesis and absorption parameters.

We questioned whether the baseline status of low-density lipoprotein cholesterol (LDL-C), cholesterol synthesis and absorption, and the changes in these parameters determine the change in serum LDL-C under statin or ezetimibe treatment or under combination treatment. 37 mildly hypercholesterolemic healthy male subjects were studied under placebo, simvastatin (20mg/d), ezetimibe (10mg/d), and combination treatment. We correlated the change of LDL-C (ΔLDL-C) under treatment with the placebo end values of LDL-C (baseline), whole-body cholesterol synthesis, and hepatic cholesterol synthesis (serum lathosterol to cholesterol ratio) as well as fractional absorption rate (FAR) of cholesterol and serum campesterol to cholesterol ratio. The change in serum LDL-C was also correlated with the changes in synthesis and absorption parameters. ΔLDL-C was highly negatively related to baseline LDL-C under ezetimibe (p<0.0001), simvastatin (p<0.0001), and combination treatment (p<0.0001). Under combination treatment, LDL-C lowering appears possible from baseline values of 10 mg/dL upwards, while ΔLDL-C was independent of the baseline value (-50 to -60%). ΔLDL-C was positively associated with placebo FAR under ezetimibe (p=0.0106) and combination treatment (p=0.0457). No associations were found between ΔLDL-C and baseline values for synthesis nor between ΔLDL-C and changes in synthesis and absorption surrogate markers. Under ezetimibe, simvastatin, and combination treatment, ΔLDL-C is predominantly dependent on the baseline LDL-C concentration. We hypothesize that the concentration gradient between serum LDL-C and hepatic cellular cholesterol determines the efficiency of serum LDL-C lowering. Combination treatment is the preferred treatment.

Integrative regulation of hLMR1 by dietary and genetic factors in nonalcoholic fatty liver disease and hyperlipidemia.

Long non-coding RNA (lncRNA) genes represent a large class of transcripts that are widely expressed across species. As most human lncRNAs are non-conserved, we recently employed a unique humanized liver mouse model to study lncRNAs expressed in human livers. We identified a human hepatocyte-specific lncRNA, hLMR1 (human lncRNA metabolic regulator 1), which is induced by feeding and promotes hepatic cholesterol synthesis. Recent genome-wide association studies (GWAS) found that several single-nucleotide polymorphisms (SNPs) from the hLMR1 gene locus are associated with blood lipids and markers of liver damage. These results suggest that dietary and genetic factors may regulate hLMR1 to affect disease progression. In this study, we first screened for nutritional/hormonal factors and found that hLMR1 was robustly induced by insulin/glucose in cultured human hepatocytes, and this induction is dependent on the transcription factor SREBP1. We then tested if GWAS SNPs genetically linked to hLMR1 could regulate hLMR1 expression. We found that DNA sequences flanking rs9653945, a SNP from the last exon of the hLMR1 gene, functions as an enhancer that can be robustly activated by SREBP1c depending on the presence of rs9653945 major allele (G). We further performed CRISPR base editing in human HepG2 cells and found that rs9653945 major (G) to minor (A) allele modification resulted in blunted insulin/glucose-induced expression of hLMR1. Finally, we performed genotyping and gene expression analyses using a published human NAFLD RNA-seq dataset and found that individuals homozygous for rs9653945-G have a higher expression of hLMR1 and risk of NAFLD. Taken together, our data support a model that rs9653945-G predisposes individuals to insulin/glucose-induced hLMR1, contributing to the development of hyperlipidemia and NAFLD.

A gut-derived hormone regulates cholesterol metabolism

The reciprocal coordination between cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver is essential for maintaining cholesterol homeostasis, yet the mechanisms governing the opposing regulation of these processes remain poorly understood. Here, we identify a hormone, Cholesin, which is capable of inhibiting cholesterol synthesis in the liver, leading to a reduction in circulating cholesterol levels. Cholesin is encoded by a gene with a previously unknown function (C7orf50 in humans; 3110082I17Rik in mice). It is secreted from the intestine in response to cholesterol absorption and binds to GPR146, an orphan G-protein-coupled receptor, exerting antagonistic downstream effects by inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver. Therefore, our results demonstrate that the Cholesin-GPR146 axis mediates the inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. This discovered hormone, Cholesin, holds promise as an effective agent in combating hypercholesterolemia and atherosclerosis.

Ganoderma lucidum polysaccharide ameliorates cholesterol gallstone formation by modulating cholesterol and bile acid metabolism in an FXR-dependent manner

BackgroundCholesterol gallstone (CG) disease is a worldwide common disease characterized by cholesterol supersaturation in gallbladder bile. Ganoderma lucidum polysaccharide (GLP) has been shown to possess various beneficial effects against metabolic disorders. However, the role and underlying mechanism of GLP in CG formation are still unknown. This study aimed to determine the role of GLP in ameliorating lithogenic diet (LD)-induced CG formation.MethodsMice were fed either a normal chow diet, a LD, or LD supplemented with GLP. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to detect the expression of genes involved in cholesterol and bile acid (BA) metabolism. The BA concentrations in the ileum were quantified by liquid chromatography-tandem mass spectrometry (LC–MS/MS). The microbiota in cecal contents were characterized using 16S ribosomal RNA (16S rRNA) gene sequencing.ResultsGLP effectively alleviated CG formation induced by LD. Specifically, GLP reduced the total cholesterol (TC) levels, increased the total BA levels, and decreased the cholesterol saturation index (CSI) in gallbladder bile. The protective effect of GLP was attributed to the inhibition of farnesoid X receptor (FXR) signaling, increased hepatic BA synthesis and decreased hepatic cholesterol synthesis and secretion. GLP also altered the BA composition in the ileum, reducing FXR-agonistic BAs and increasing FXR-antagonistic BAs, which may contribute to the inhibition of intestinal FXR signaling. Additionally, GLP improved dysbiosis of the intestinal flora and reduced the serum levels of hydrogen sulfide (H2S), a bacterial metabolite that can induce hepatic FXR, thereby inhibiting hepatic FXR signaling. Moreover, the protective effect of GLP against CG formation could be reversed by both the global and gut-restricted FXR agonists.ConclusionsTaken together, GLP ameliorates CG formation by regulating cholesterol and BA metabolism in an FXR-dependent manner. Our study demonstrates that GLP may be a potential strategy for the prevention against CG disease.

Therapeutic Role of Polyphenol Extract from Prunus cerasifera Ehrhart on Non-Alcoholic Fatty Liver.

Prunus cerasifera Ehrhart (P. cerasifera) flourishes uniquely in the arid landscapes of Xinjiang, China. Preliminary studies have revealed the therapeutic potential of its polyphenol extract (PPE) in mitigating liver lipid accumulation in mice fed a high-fat diet. We established a mouse model that was subjected to a continuous high-fat diet for 24 weeks and administered PPE to investigate the effects of PPE on cholesterol and BA metabolism in NAFLD mice. The results showed that PPE administration (200 and 400 mg/kg/day, BW) led to a reduction in liver TC, an increase in liver T-BAs, and normalization of the disrupted fecal BA profile. Concurrently, it decreased levels of lipotoxic BAs and inhibited hepatic cholesterol synthesis (evidenced by reduced HMGCR activity) and intestinal cholesterol absorption (indicated by lower ACAT2 levels) while enhancing intestinal cholesterol efflux (via LXRα, ABCA1, ABCG5, and ABCG8) and stimulating hepatic BA synthesis (CYP7A1, CYP27A1) and secretion (BSEP). PPE thus led to a significant reduction in lipotoxic BAs metabolized by gut microbiota and a downregulation of the BA secretion pathway under its influence. Our findings reveal the therapeutic effect of PPE on NAFLD mice via regulating cholesterol and BA metabolism, providing a theoretical basis for exploring the potential functions of P. cerasifera.

Replacement of dietary carbohydrate with protein increases fat mass and reduces hepatic triglyceride synthesis and content in female obese Zucker rats.

Previous studies have demonstrated both energy restriction (ER) and higher protein (HP), lower carbohydrate (LC) diets downregulate hepatic de novo lipogenesis. Little is known about the independent and combined impact of ER and HP/LC diets on tissue-specific lipid kinetics in leptin receptor-deficient, obese rodents. This study investigated the effects of ER and dietary macronutrient content on body composition; hepatic, subcutaneous adipose tissue (SAT), and visceral AT (VAT) lipid metabolic flux (2 H2 O-labeling); and blood and liver measures of cardiometabolic health in six-week-old female obese Zucker rats (Leprfa+/fa+ ). Animals were randomized to a 10-week feeding intervention: adlibitum (AL)-HC/LP (76% carbohydrate/15% protein), AL-HP/LC (35% protein/56% carbohydrate), ER-HC/LP, or ER-HP/LC. ER groups consumed 60% of the feed consumed by AL. AL gained more fat mass than ER (P-energy = 0.012) and HP/LC gained more fat mass than HC/LP (P-diet = 0.025). Hepatic triglyceride (TG) concentrations (P-interaction = 0.0091) and absolute hepatic TG synthesis (P-interaction = 0.012) were lower in ER-HP/LC versus ER-HC/LP. ER had increased hepatic, SAT, and VAT de novo cholesterol fractional synthesis, absolute hepatic cholesterol synthesis, and serum cholesterol (P-energy≤0.0035). A HP/LC diet, independent of energy intake, led to greater gains in fat mass. A HP/LC diet, in the context of ER, led to reductions in absolute hepatic TG synthesis and TG content. However, ER worsened cholesterol metabolism. Increased adipose tissue TG retention with the HP/LC diet may reflect improved lipid storage capacity and be beneficial in this genetic model of obesity.

MicroRNA-206-3p suppresses hepatic lipogenesis and cholesterol synthesis while driving cholesterol efflux.

Hepatosteatosis, hypertriglyceridemia, and hypertriglyceridemia are interconnected metabolic disorders. This study is designed to characterize how microRNA-206-3p (miR-206) simultaneously prevents de novo lipogenesis (DNL), cholesterol synthesis, and VLDL production in hepatocytes while promoting cholesterol efflux in macrophages. MiR-206 levels were reduced in hepatocytes and macrophages of mice subjected to a high-fat, high-cholesterol diet (HFHC). A negative feedback between LXRα (liver X receptor) and miR-206 is formed to maintain high LXRα and low miR-206 in hepatocytes. Systemic administration of miR-206 alleviated hepatosteatosis, hypertriglyceridemia and hypercholesterolemia in mice. A significant reduction in LDL-cholesterol and VLDL-cholesterol but unaltered HDL-cholesterol was observed in miR-206-treated mice. Mirroring these findings, miR-206 reprogrammed the transcriptome of hepatocytes towards inhibition of DNL, cholesterol synthesis, and assembly and secretion of VLDL. In macrophages, miR-206 activated expression of genes regulating cholesterol efflux. Hepatocyte-specific expression of miR-206 reduced hepatic and circulating triglycerides and cholesterol as well as VLDL production, while transplantation of macrophages bearing miR-206 facilitated cholesterol efflux. Mechanistically, miR-206 directly targeted Lxrα and Hmgcr in hepatocytes but facilitated expression of Lxrα in macrophages by targeting macrophage-specific TRPS1 (tricho-rhino-phalangeal syndrome 1), a transcription repressor of Lxrα. By targeting Hmgcr and Lxrα, miR-206 inhibited DNL, VLDL production and cholesterol synthesis in hepatocytes, whereas it drove cholesterol efflux by activating the TRPS1-LXRα axis. MiR-206, through differentially modulating LXRα signaling in hepatocytes and macrophages, inhibits DNL, promotes cholesterol efflux, and concurrently hinders cholesterol synthesis and VLDL production. MiR-206 simulates the functions of lipid-lowering medications, statins and LXRα agonists.

Electroacupuncture regulates hepatic cholesterol synthesis by HMGCR deubiquitination in rats

This experiment was designed to explore the effect and mechanism of electroacupuncture (EA) for hyperlipidemia and hepatic cholesterol synthesis in rats. Liver and adipose tissues were assessed histologically, and body and liver weight, serum and liver lipid levels, expression of mTOR/ubiquitin-specific peptidase 20 (USP20)/recombinant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and phosphorylation of mTOR and USP20 were measured. In vitro deubiquitination assays with liver cytosol were conducted. EA at Fenglong point ameliorated hyperlipidemia and hepatocyte steatosis, and decreased p-USP20, p-mTOR and HMGCR expression in the liver by reducing deubiquitination. Furthermore, EA decreased feeding-induced lipid biosynthesis in the liver. Concomitantly, EA prevented the induction of phosphorylated USP20 and mTOR, and HMGCR expression; and reduced the deubiquitination of HMGCR after re-feeding. This experiment demonstrated that EA can effectively improve hyperlipidemia and reduce hepatic cholesterol synthesis by counteracting the deubiquitination activity of HMGCR in hyperlipidemic rats.

Protective Effects of Melatonin in High-Fat Diet-Induced Hepatic Steatosis via Decreased Intestinal Lipid Absorption and Hepatic Cholesterol Synthesis.

The preventative effect of melatonin on the development of obesity and the progression of fatty liver under a high-fat diet (HFD) has been well elucidated through previous studies. We investigated the mechanism behind this effect regarding cholesterol biosynthesis and regulation of cholesterol levels. Mice were divided into three groups: normal chow diet (NCD); HFD; and HFD and melatonin administration group (HFD+M). We assessed the serum lipid profile, mRNA expression levels of proteins involved in cholesterol synthesis and reabsorption in the liver and nutrient transporters in the intestines, and cytokine levels. Additionally, an in vitro experiment using HepG2 cells was performed. Expression of hepatic sterol regulatory element-binding protein 2 (SREBP-2), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and low-density lipoprotein receptor (LDLR) demonstrated that melatonin administration significantly reduces hepatic cholesterol synthesis in mice fed an HFD. Expression of intestinal sodium-glucose transporter 1 (SGLT1), glucose transporter 2 (GLUT2), GLUT5, and Niemann-pick C1-like 1 (NPC1L1) demonstrated that melatonin administration significantly reduces intestinal carbohydrate and lipid absorption in mice fed an HFD. There were no differences in local and circulatory inflammatory cytokine levels among the NCD, HFD, and HFD+M group. HepG2 cells stimulated with palmitate showed reduced levels of SREBP, LDLR, and HMGCR indicating these results are due to the direct mechanistic effect of melatonin on hepatocytes. Collectively, these data indicate the mechanism behind the protective effects of melatonin from weight gain and liver steatosis under HFD is through a reduction in intestinal caloric absorption and hepatic cholesterol synthesis highlighting its potential in the treatment of obesity and fatty liver disease.

Association between Familial Hypercholesterolemia and Serum Levels of Cholesterol Synthesis and Absorption Markers: The CACHE Study FH Analysis.

Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Familial hypercholesterolemia (FH) is a well-known inherited disorder presenting elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels and premature coronary disease. In this study, we aim to examine the differences in terms of serum markers of cholesterol metabolism between FH and non-FH individuals and to examine their associations with serum lipid levels. In this study, we utilized data on serum markers of cholesterol metabolism, namely, lathosterol (Latho, synthesis marker), campesterol (Campe, absorption marker), and sitosterol (Sito, absorption marker) measured by gas chromatography of the CACHE consortium, which comprised of 13 research groups in Japan. Clinical data were compiled using REDCap system. Among the 2944 individuals in the CACHE population, we selected individuals without lipid-lowering medications and hemodialysis patients for this CACHE study FH analysis. Multivariable adjustment was performed to assess the associations. In this study, we analyzed data from 51 FH patients and 1924 non-FH individuals. After adjustment for possible confounders, the FH group was shown to have significantly higher Campe and Sito concentrations and insignificantly higher Latho concentrations than the non-FH group. These marker concentrations showed nonlinear associations with TC in the FH group. Campe/Latho and Sito/Latho ratios were significantly higher in the FH group than in the non-FH group. FH group had significantly elevated serum Campe and Sito concentrations and insignificantly elevated Latho concentrations; thus, intestinal cholesterol absorption relative to hepatic cholesterol synthesis was suggested to be elevated in patients with FH. Serum Latho, Campe, and Sito concentrations showed nonlinear associations with TC in the FH group.

Differential expression of lipid metabolic genes in hypercholesterolemic rabbit placenta predisposes the offspring to develop atherosclerosis in early adulthood

AimsMaternal hypercholesterolemia (MHC) is a pathological condition that may cause atherosclerosis in the adulthood of the offspring. The study aims to identify the role of in-utero programming by the placenta in atherogenesis and associated liver pathology in offspring. Main methodsFemale New Zealand white rabbits with normal lipid profiles were fed a 0.3 % HFD after mating. Lipid levels were monitored, and pregnant rabbits were sacrificed at the end of trimester 1, trimester 2, and trimester 3. Placental histology and expression of lipid metabolism genes were studied. Lipid levels, aortic lesions, and mRNA expression of cholesterol synthesis genes were investigated in fetuses at the end of gestation. A group of fetuses was allowed to attain early adulthood to investigate the liver lipid metabolism and atherogenesis with and without an HFD. Key findingsElevated maternal lipid levels and placental gene expression were differentially modulated in HFD-fed mothers. HFD-fed rabbits demonstrated differential expression of the placental genes involved in receptor-mediated endocytosis of cholesterol, lipogenesis, and lipolysis in all three trimesters. It resulted in significant lipid depositions in the placenta, hyperlipidemia, and a decrease in hepatic cholesterol synthesis in fetuses at the end of gestation. There was no atherogenesis in the aorta of offspring at trimester 3, but such offspring of HFD-fed mothers developed atherosclerosis and non-alcoholic fatty liver (NAFL) with profound steatosis in their early adulthood with and without HFD. SignificanceDiet-induced MHC differentially expressed placental lipid genes that may program the offspring to develop atherosclerosis and associated NAFL in early adulthood.

Gypenosides ameliorate high-fat diet-induced nonalcoholic fatty liver disease in mice by regulating lipid metabolism.

Gypenosides (GP), extracted from the traditional Chinese herb Gynostemma pentaphyllum (Thunb.) Makino, have been used to treat metabolic disorders, including lipid metabolism disorders and diabetes. Although recent studies have confirmed their beneficial effects in nonalcoholic fatty liver disease (NAFLD), the underlying therapeutic mechanism remains unclear. In this study, we explored the protective mechanism of GP against NAFLD in mice and provided new insights into the prevention and treatment of NAFLD. Male C57BL6/J mice were divided into three experimental groups: normal diet, high-fat diet (HFD), and GP groups. The mice were fed an HFD for 16 weeks to establish an NAFLD model and then treated with GP for 22 weeks. The transcriptome and proteome of the mice livers were profiled using RNA sequencing and high-resolution mass spectrometry, respectively. The results showed that GP decreased serum lipid levels, liver index, and liver fat accumulation in mice. Principal component and heatmap analyses indicated that GP significantly modulated the changes in the expression of genes associated with HFD-induced NAFLD. The 164 differentially expressed genes recovered using GP were enriched in fatty acid and steroid metabolism pathways. Further results showed that GP reduced fatty acid synthesis by downregulating the expression of Srebf1, Fasn, Acss2, Acly, Acaca, Fads1, and Elovl6; modulated glycerolipid metabolism by inducing the expression of Mgll; promoted fatty acid transportation and degradation by inducing the expression of Slc27a1, Cpt1a, and Ehhadh; and reduced hepatic cholesterol synthesis by downregulating the expression of Tm7sf2, Ebp, Sc5d, Lss, Fdft1, Cyp51, Nsdhl, Pmvk, Mvd, Fdps, and Dhcr7. The proteomic data further indicated that GP decreased the protein expression levels of ACACA, ACLY, ACSS2, TM7SF2, EBP, FDFT1, NSDHL, PMVK, MVD, FDPS, and DHCR7 and increased those of MGLL, SLC27A1, and EHHADH. In conclusion, GP can regulate the key genes involved in hepatic lipid metabolism in NAFLD mice, providing initial evidence for the mechanisms underlying the therapeutic effect of GP in NAFLD.

Pectin Feeding Influences Fecal Bile Acid Excretion, Hepatic Bile Acid and Cholesterol Synthesis and Serum Cholesterol in Rats

This study was designed to investigate the effects of pectin on cholesterol and bile acid metabolism and to elucidate the mechanisms involved in its hypolipidemic effect in rats. The key regulatory enzymes in cholesterol and bile acid metabolism, 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and cholesterol 7α-hydroxylase, were determined. Circulating, hepatic, and biliary lipid concentrations and fecal bile acid excretion were also measured. Male Wistar rats were fed a fiber-free or a pectin-supplemented (7 g/100 g) diet for 4 wk. Bile flow and the biliary secretion of both bile acids and cholesterol were not significantly different than controls in pectin-fed rats. The addition of pectin to the diet resulted in lower serum and liver cholesterol concentrations (-27 and -17%, respectively). Fecal bile acid excretion (+168%) and the hepatic activity of cholesterol 7α-hydroxylase (+70%) were significantly higher in pectin-fed animals. HMG-CoA reductase activity was also significantly greater (+11%) in the presence of dietary pectin. Results of our study indicate that pectin, by enhancing fecal bile acid excretion, may cause increased hepatic synthesis of bile acids and liver depletion of cholesterol in rats, which results in a higher rate of cholesterol synthesis and reduced serum cholesterol concentrations.

Neutral effect of SGLT2 inhibitors on lipoprotein metabolism: From clinical evidence to molecular mechanisms

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective, well-tolerated, and safe glucose-lowering compounds for patients with type 2 diabetes mellitus (T2DM). SGLT2i benefit encompasses protection from heart and kidney failure, independently of the presence of diabetes. In addition, SGLT2i consistently reduce the risk of hospitalization for heart failure and, although with some heterogeneity between specific members of the class, favourably affect the risk of cardiovascular outcomes. The molecular mechanisms underlying the cardiovascular favourable effect are not fully clarified. Studies testing the efficacy of SGLT2i in human cohorts and experimental models of atherosclerotic cardiovascular disease (ASCVD) have reported significant differences in circulating levels and composition of lipoprotein classes. In randomized clinical trials, small but significant increases in low-density lipoprotein cholesterol (LDL-C) levels have been observed, with a still undefined clinical significance; on the other hand, favourable (although modest) effects on high-density lipoprotein cholesterol (HDL-C) and triglycerides have been reported. At the molecular level, glycosuria may promote a starving-like state that ultimately leads to a metabolic improvement through the mobilization of fatty acids from the adipose tissue and their oxidation for the production of ketone bodies. This, however, may also fuel hepatic cholesterol synthesis, thus inhibiting atherogenic lipoprotein uptake from the liver. Long-term studies collecting detailed information on lipid-lowering therapies at baseline and during the trials with SGLT2i, as well as regularly monitoring lipid profiles are warranted to disentangle the potential implications of SGLT2i in modulating lipoprotein-mediated atherosclerotic cardiovascular risk.

Long noncoding RNA lincsc5d regulates hepatic cholesterol synthesis by modulating sterol C5 desaturase in large yellow croaker.

Although long noncoding RNA (lncRNA) plays a vital role in cholesterol metabolism, very little information is available in fish. Thus, a 10-week feeding experiment was performed to estimate the effects of lncRNA on cholesterol metabolism in large yellow croaker fed with fish oil (FO), soybean oil (SO), olive oil (OO), and palm oil (PO) diets. Results showed that fish fed with OO and PO diets had higher liver total cholesterol (TC) and cholesterol ester (CE) contents compared with fish fed with FO diets. Analysis of the KEGG pathway showed that the steroid biosynthesis pathway was enriched in comparisons FO vs SO, FO vs OO, and FO vs PO. Meanwhile, sterol C5 desaturase (SC5D), a cholesterol synthase, was up-regulated in the steroid biosynthesis pathway. SC5D was widely expressed in all tissues examined, and the highest expression of SC5D was detected in brain. More importantly, a novel lncRNA associated with sc5d gene was identified by RNA sequencing and named as lincsc5d. The tissue distribution of lincsc5d was similar to that of sc5d. A nuclear/cytoplasmic RNA separation assay showed that lincsc5d was a nucleus-enriched lncRNA. qRT-PCR results demonstrated that lincsc5d was markedly up-regulated in the SO, OO, and PO groups. Furthermore, the results of TC content and the lincsc5d and sc5d expression in hepatocytes agreed with in vivo results. In conclusion, this study indicated that vegetable oils, especially OO and PO, increased hepatic cholesterol levels by promoting cholesterol synthesis, and lncRNA lincsc5d and sc5d might be involved in cholesterol synthesis.

Bempedoic Acid: Lipid Lowering for Cardiovascular Disease Prevention.

The management of low-density lipoprotein cholesterol (LDL-C) levels is a central strategy for the prevention of atherosclerotic cardiovascular disease. Current United States (2018 American Heart Association/American College of Cardiology/Multisociety) and European (2019 European Society of Cardiology/European Atherosclerosis Society) guidelines endorse statin therapy as the first-line therapy for pharmacologic LDL-C lowering. However, in clinical practice up to 30% of patients report partial or complete intolerance to statin therapy. While the nocebo effect with statins is well described, perceived statin intolerance prevents many patients from achieving LDL-C thresholds associated with clinical benefit. Bempedoic acid is a novel, oral, non-statin lipid-l owering therapy that works by inhibiting adenosine triphosphate-citrate lyase, an enzymatic reaction upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the hepatic cholesterol synthesis pathway. Bempedoic acid confers reduction in LDL-C of ~18% on background statin therapy,~21% in patients with statin intolerance, and ~38% when given in fixed-dose combination with ezetimibe. The CLEAR Outcomes trial, which enrolled high-risk primary and secondary prevention patients with reported statin intolerance and LDL-C levels ≥100 mg/dL, showed that bempedoic acid compared with placebo reduced 4-component major adverse cardiovascular events (MACE) by 13% (hazard ratio 0.87, 95% confidence interval 0.79-0.96). Bempedoic acid also reduced 3-component MACE by 15%, myocardial infarction by 23% and coronary revascularization by 19%. The benefit was even greater in the primary prevention cohort (hazard ratio 0.70, 95% confidence interval 0.55-0.89) for 4-component MACE. Bempedoic acid was associated with increases in uric acid levels and cholelithiasis, but numerically fewer events of myalgia and new-onset diabetes. These findings confirm that bempedoic acid is an effective approach to reduce cardiovascular outcomes in high-risk patients with statin intolerance who require further reduction in LDL-C.

Atorvastatin remodels lipid distribution between liver and adipose tissues through blocking lipoprotein efflux in fish.

The regulation of cholesterol metabolism in fish is still unclear. Statins play important roles in promoting cholesterol metabolism development in mammals. However, studies on the role of statins in cholesterol metabolism in fish are currently limited. The present study evaluated the effects of statins on cholesterol metabolism in fish. Nile tilapia (Oreochromis niloticus) were fed on control diets supplemented with three atorvastatin levels (0, 12, and 24 mg/kg diet, ATV0, ATV12, and ATV24, respectively) for 4 wk. Intriguingly, the results showed that both atorvastatin treatments increased hepatic cholesterol and triglyceride contents mainly through inhibiting bile acid synthesis and efflux, and compensatorily enhancing cholesterol synthesis in fish liver (P < 0.05). Moreover, atorvastatin treatment significantly inhibited hepatic very-low-density lipoprotein (VLDL) assembly and thus decreased serum VLDL content (P < 0.05). However, fish treated with atorvastatin significantly reduced cholesterol and triglycerides contents in adipose tissue (P < 0.05). Further molecular analysis showed that atorvastatin treatment promoted cholesterol synthesis and lipogenesis pathways, but inhibited lipid catabolism and low-density lipoprotein (LDL) uptake in the adipose tissue of fish (P < 0.05). In general, atorvastatin induced the remodeling of lipid distribution between liver and adipose tissues through blocking VLDL efflux from the liver to adipose tissue of fish. Our results provide a novel regulatory pattern of cholesterol metabolism response caused by atorvastatin in fish, which is distinct from mammals: cholesterol inhibition by atorvastatin activates hepatic cholesterol synthesis and inhibits its efflux to maintain cholesterol homeostasis, consequently reduces cholesterol storage in fish adipose tissue.

Cystic Fibrosis Patients with F508del/Minimal Function Genotype: Laboratory and Nutritional Evaluations after One Year of Elexacaftor/Tezacaftor/Ivacaftor Treatment.

The last ten years have been characterized by an enormous step forward in the therapy and management of patients with Cystic Fibrosis (CF), thanks to the development and combination of Cystic Fibrosis Transmembrane Receptor (CFTR) correctors and potentiators. Specifically, the last approved triple combination elexacaftor/tezacaftor/ivacaftor has been demonstrated to improve lung function in CF patients with both homozygous Phe508del and Phe508del/minimal function genotypes. Here we have assessed the effect of elexacaftor/tezacaftor/ivacaftor in patients carrying the Phe508del/minimal function genotype (n = 20) after one year of treatments on liver function and nutrient absorption with a focus on lipid metabolism. We show that weight, BMI, and albumin significantly increase, suggesting a positive impact of the treatment on nutrient absorption. Furthermore, cholesterol levels as a biomarker of lipid metabolism increased significantly after one year of treatment. Most importantly, we suggest that these results were not dependent on the diet composition, possibly indicating that the drug improves the hepatic synthesis and secretion of proteins and cholesterol.

MiR-133a-3p/Sirt1 epigenetic programming mediates hypercholesterolemia susceptibility in female offspring induced by prenatal dexamethasone exposure

Mounting evidence indicates that adverse intrauterine conditions increase offspring’s hypercholesterolemia susceptibility in adulthood. This study aimed to confirm prenatal dexamethasone exposure (PDE)-induced hypercholesterolemia susceptibility in female adult offspring rats, and elucidate its intrauterine programming mechanism. Pregnant Wistar rats were injected with dexamethasone subcutaneously (0, 0.1 and 0.2 mg/kg·d) from gestational day (GD) 9 to 20. Serum and liver of the female offspring were collected at GD21 and postnatal week (PW) 12 and 28. PDE offspring showed elevated serum total cholesterol (TCH) levels and a cholesterol phenotype of high cardiovascular disease risk at PW12 and PW28. The histone acetylation levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) and its expression were consistently increased in the PDE offspring both in utero and after birth. Moreover, PDE promoted glucocorticoid receptor (GR) nuclear translocation and miR-133a-3p expression and inhibited sirtuin-1 (Sirt1) expression in the fetal liver. In vitro, dexamethasone increased intracellular and supernatant TCH levels and miR-133a-3p expression, decreased SIRT1 expression, and promoted HMGCR histone acetylation and expression in bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and HepG2 cell line. GR siRNA, miR-133a-3p inhibitor or SIRT1 overexpression reversed dexamethasone-induced downstream molecular and phenotypic changes. Furthermore, elevated TCH levels in umbilical cord blood and increased HMGCR expression in peripheral blood mononuclear cells (PBMCs) were observed in human female neonates who had received dexamethasone treatment during pregnancy. In conclusion, PDE can cause persistent enhancement of hepatic cholesterol synthesis function before and after birth through GR/miR-133a-3p/Sirt1 pathway, eventually leading to increased hypercholesterolemia susceptibility in female offspring rats.

Abstract P3132: High-salt Diet Increases Blood Cholesterol: Potential Role Of Hepatic Enzyme CYP51

Introduction: The increased consumption of dietary fat has been well established to lead to cardiovascular disease via the elevation of lipids in serum. High blood pressure is also commonly associated with high serum cholesterol levels, but the relationships among blood pressure, dietary sodium intake and serum cholesterol have not been fully elucidated. Hypothesis: An increase in the intake of salt causes an elevation of serum cholesterol through the activation of hepatic enzymes critical to cholesterol synthesis. Methods: Dahl salt-sensitive rats (n=6) were fed a high-salt (HS) diet (8% NaCl) from 7 weeks of age to induce hypertension. Rats fed a normal-salt (NS) diet (0.3% NaCl; n=6) served as controls. Blood pressure was measured non-invasively using a tail artery cuff. Blood was withdrawn from 6-hour fasting HS and NS-fed rats to check serum cholesterol levels. Low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very-low density lipoprotein (VLDL) cholesterols were measured. Gene expression array and western blot were performed in liver protein extracts from HS and NS-fed rats. Results: Systolic blood pressure was elevated in HS-fed rats compared to NS-fed rats at 16 weeks of age (225±23 vs. 156±18 mmHg, p=0.0002). Serum fasting cholesterol was higher in hypertensive rats compared to normotensive rats (194±49 vs. 102±12 mg/dL, p=0.0013). LDL cholesterol was higher in HS-fed rats compared to NS-fed rats (83±9 vs. 60±10 mg/dL, p=0.0024), while HDL and VLDL cholesterol were not. Hepatic cholesterol synthesis gene array revealed significant up-regulation of 3 genes in hypertensive rats in comparison to normotensive rats ( Apoa1 fold change [FC] 2.84, p&lt;0.0001; Tm7sf2 FC 2.45, p=0.0004; Cyp51 FC 2.44, p=0.0002). Western blot of hepatic protein extracts showed a definitive increase in CYP51 in HS-fed rats compared to NS-fed rats (normalized against GAPDH, 2.7-fold increase, p=0.0018). Conclusions: A high-salt diet increased serum cholesterol levels, potentially via activation of liver enzyme CYP51, which is crucial for the synthesis of cholesterol in the liver. Further research is warranted to investigate the mechanisms of how high-salt diets can increase CYP51 in the liver.