Absorption Of Dietary Cholesterol Research Articles

PA01.53. Flax seed oil role in hypercholesterolemia

Purpose: To study the role of flax seed oil in hypercholesterolemia. Abnormal lipid metabolism is a main cause of dyslipidaemia, which is a major risk factor for cardiovascular disease, obesity, cholesthiasis and overall mortality. The concentration of plasma cholesterol can be regulated by cholesterol biosynthesis, removal of cholesterol from the circulation, absorption of dietary cholesterol and excretion of cholesterol via bile and faeces. In liver, such lipid accumulation initially results in fatty liver that develops fatty infiltration and in chronic stages results in damage of hepatocytes, that causes gross fatty infiltration in parenchyma cells of liver. It is well known that diet plays an important role in the control of cholesterol homeostasis. In this context, it has been reported that herbs have been used as food and for medicinal purpose for hyperlipidaemia that may be useful in reducing the risk of cardiovascular disease and alterations in liver metabolism. Method: This Study was carried out on 30 Patients of Hypercholesterolemia, of which 18 were Female and 12 were male patients. All the Patients were selected for the study after Blood Test for Complete Lipid Profile. The study was carried out at OPD level of D2S Ayurveda Clinic Jaipur an Urban Clinic, for the period of 6 Months. 2 capsules of flaxseed oil were given twice daily. Result: Result assessment according to overall response to the period and in the level of Blood reports of HDL, LDL, triglycerides. Results were analysed in form of Nil, Poor, Moderate, Good response to the treatment. It was seen that among 30 Patients 13 got Good response, 12 got Moderate response, 5 got poor response among these LDL cholesterol levels were moderately reduced, Triglycerides mildly reduced, whereas HDL cholesterol levels increased significantly. Conclusion: The current study proved the efficiency of flax seed oil on hypercholesterolemia.

Chemical composition and physicochemical characteristics of fixed oils from algerian Nigella sativa seeds

The fatty acids, sterols, and polyphenols from the fixed oils of Nigella sativa seeds originating from four locations were determined. The seeds contained respectively 30.63–34.27% and 25.66–32.77% of fixed oils using hexane and isopropyl alcohol in solvent extraction. Linoleic, oleic, and palmitic acids formed the main proportion using the two solvents, respectively: hexane 54.47–61.28%, isopropanol 56.98–67.30%; hexane 19.62–22.94%, isopropanol 18.85–21.96%, and hexane 11.17–13.60%, isopropanol 9.20–14.18%. Other minor unsaturated fatty acids were identified. Eight phytosterols were isolated and identified in the fixed oils by GC and GC/MS analysis, wherein I²-sitosterol was the dominating compound that inhibits the absorption of dietary cholesterol, followed by stigmasterol, campesterol, and I”5-avenasterol.

Progress in the Mechanism of Dietary Cholesterol Absorption

Niemann Pick C1 Like 1(NPC1L1),a polytopic transmembrane protein,is a key protein that mediates the enterohepatic absorption of free cholesterol from diet and bile.In this article,we reviewed the function,structure and working mechanism of NPC1L1.NPC1L1 associates with lipid raft proteins Flotillin-1 or Flotillin-2 to form the cholesterol-enriched membrane microdomains on the plasma membrane.The microdomains are endocytosed and transported to the intercellular endocytic recycling compartment(ERC) via vesicular endocytosis pathway mediated by clathrin/AP2 complex.Cholesterol depletion leads to the transport of NPC1L1-Flotillin complex from ERC to plasma membrane,during which Cdc42 and the Myosin Vb.Rab11a.Rab11-FIP2 triple complex play crucial roles,and then the plasma membrane-localized NPC1L1 specifically binds exogenous cholesterol via its N-terminal domain(NTD),which is necessary for the formation of NPC1L1-flotillin-cholesterol membrane microdomain.Nonsynonymous variants of NPC1L1 in humans are suggested to associate with abnormal cholesterol absorption.We also summarized some of the remaining questions and proposed future directions for this research.

Intestinal sterol transporters and cholesterol absorption inhibition

Statin therapy is the mainstay of lipid-lowering therapy; however, many patients, particularly those at high risk, do not achieve sufficient LDL-cholesterol (LDL-C) lowering. Thus, there remains an unmet medical need for more effective and well tolerated lipid-lowering agents. Guidelines recommend combining additional lipid-lowering agents with a complementary mode of action for these patients. One approach to complementing statin therapy is combination with inhibitors that block the intestinal absorption of dietary and biliary cholesterol. This review summarizes what is currently known about intestinal sterol transporters and cholesterol absorption inhibitors (CAIs). The only lipid-lowering agent currently available that specifically targets an intestinal sterol transporter (Niemann-Pick C1-like 1) is the CAI, ezetimibe. It is effective in lowering LDL-C, both when given alone and when combined with a statin. Clinical outcome data with ezetimibe combined with simvastatin have recently become available, and definitive evidence that the incremental LDL-C lowering attributable to the ezetimibe component reduces cardiovascular events beyond simvastatin alone is currently under study. Other novel CAIs have been evaluated based upon the structure and properties of ezetimibe, but none remain in development. Additional lipid-lowering agents are needed to fulfill an unmet medical need for those patients who do not achieve optimal LDL-C goals on statin monotherapy. The inhibition of cholesterol absorption is an important therapeutic strategy to reduce cholesterol levels. Based upon the demonstrated lipid-altering efficacy and safety of ezetimibe, several CAIs have been identified; all to date have been discontinued due to limited efficacy.

The Small GTPase Cdc42 Interacts with Niemann-Pick C1-like 1 (NPC1L1) and Controls Its Movement from Endocytic Recycling Compartment to Plasma Membrane in a Cholesterol-dependent Manner

Niemann-Pick C1-like 1 (NPC1L1) is a multi-transmembrane protein that mediates the absorption of dietary and biliary cholesterol through vesicular endocytosis. The subcellular localization of NPC1L1 is regulated by cholesterol. Cholesterol depletion induces the transport of NPC1L1 to plasma membrane (PM) from endocytic recycling compartment that requires MyoVb·Rab11a·Rab11-FIP2 triple complex, and cholesterol-replenishment renders the internalization of NPC1L1 together with cholesterol. Here, we find that GTP-bound Cdc42 interacts with NPC1L1. Cholesterol depletion regulates the activation of Cdc42 and enhances NPC1L1-Cdc42 interaction. Overexpression of constitutive GTP-bound Cdc42 mutant form or knockdown of Cdc42 inhibits the transport of NPC1L1 to the PM and disturbs the cholesterol-regulated binding of NPC1L1 to Rab11a, MyoVb, and actin. Knockdown of Cdc42 downstream effectors N-WASP or Arp3 also leads to the similar results. In liver-specific Cdc42 knock-out (Cdc42 LKO) mice, NPC1L1 fails to localize to bile canaliculi, and the biliary cholesterol cannot be efficiently reabsorbed. These results indicate that Cdc42 controls the cholesterol-regulated transport and localization of NPC1L1, and plays a role in cholesterol absorption.

The Role of Bile Acid Excretion in Atherosclerotic Coronary Artery Disease

The impact of cholesterol and different classes of lipoproteins on the development of coronary artery disease (CAD) has been investigated in extensively during the past 50 years. The cholesterol metabolism is dependent on numerous factors, including dietary fat, fractional absorption of dietary cholesterol, tissue stores of cholesterol, endogenous cholesterol synthesis, and fecal bile excretion. Several studies showed significantly lower amounts of bile acid secretion in adult patients with CAD compared to non-CAD patients. Could it be that the inability to efficiently excrete bile acids may lead to CAD development?

The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake

Niemann-Pick C1-like 1 (NPC1L1) is a multitransmembrane protein playing a crucial role in dietary and biliary cholesterol absorption. Cholesterol promotes the formation and endocytosis of NPC1L1-flotillin-cholesterol membrane microdomains, which is an early step in cholesterol uptake. How cholesterol is sensed in this step is unknown. Here, we find that the N-terminal domain (NTD) of NPC1L1 binds cholesterol. Mutation of residue Leu-216 in NPC1L1-NTD eliminates cholesterol binding, decreases the formation of NPC1L1-flotillin-cholesterol membrane microdomains, and prevents NPC1L1-mediated cholesterol uptake in culture cells and mice livers. NPC1L1-NTD specifically binds cholesterol but not plant sterols, which may account for the selective cholesterol absorption in intestine. Furthermore, 25- or 27-hydroxycholesterol competes with cholesterol to bind NPC1L1-NTD and inhibits the cholesterol induced endocytosis of NPC1L1. Together, these results demonstrate that plasma membrane-localized NPC1L1 binds exogenous cholesterol via its NTD, and facilitates the formation of NPC1L1-flotillin-cholesterol membrane microdomains that are then internalized into cells through the clathrin-AP2 pathway. Our study uncovers the mechanism of cholesterol sensing by NPC1L1 and proposes a mechanism for selective cholesterol absorption.

Intestinal SR-BI is upregulated in insulin-resistant states and is associated with overproduction of intestinal apoB48-containing lipoproteins

Intestinal lipid dysregulation is a common feature of insulin-resistant states. The present study investigated alterations in gene expression of key proteins involved in the active absorption of dietary fat and cholesterol in response to development of insulin resistance. Studies were conducted in two diet-induced animal models of insulin resistance: fructose-fed hamster and high-fat-fed mouse. Changes in the mRNA abundance of lipid transporters, adenosine triphosphate cassette (ABC) G5, ABCG8, FA-CoA ligase fatty acid translocase P4, Niemann-Pick C1-Like1 (NPC1L1), fatty acid transport protein 4 (FATP4), and Scavenger Receptor Class B Type I (SR-BI), were assessed in intestinal fragments (duodenum, jejunum, and ileum) using quantitative real-time PCR. Of all the transporters evaluated, SR-B1 showed the most significant changes in both animal models examined. A marked stimulation of SR-B1 expression was observed in all intestinal segments examined in both insulin-resistant animal models. The link between SR-BI expression and intestinal lipoprotein production was then examined in the Caco-2 cell model. SR-B1 overexpression in Caco-2 cells increased apolipoprotein B (apoB) 100 and apoB48 secretion, whereas RNAi knock down of SR-B1 decreased secretion of both apoB100 and apoB48. We also observed changes in subcellular distribution of SR-B1 in response to exogenous lipid and insulin. Confocal microscopy revealed marked changes in SR-BI subcellular distribution in response to both exogenous lipids (oleate) and insulin. In summary, marked stimulation of intestinal SR-BI occurs in vivo in animal models of diet-induced insulin resistance, and modulation of SR-BI in vitro regulates production of apoB-containing lipoprotein particles. We postulate that apical and/or basolateral SR-BI may play an important role in intestinal chylomicron production and may contribute to chylomicron overproduction normally observed in insulin-resistant states.

Kinetic properties of mouse pancreatic lipase-related protein-2 suggest the mouse may not model human fat digestion

Genetically engineered mice have been employed to understand the role of lipases in dietary fat digestion with the expectation that the results can be extrapolated to humans. However, little is known about the properties of mouse pancreatic triglyceride lipase (mPTL) and pancreatic lipase-related protein-2 (mPLRP2). In this study, both lipases were expressed in Pichia Pastoris GS115, purified to near homogeneity, and their properties were characterized. Mouse PTL displayed the kinetics typical of PTL from other species. Like mPTL, mPLRP2 exhibited strong activity against various triglycerides. In contrast to mPTL, mPLRP2 was not inhibited by increasing bile salt concentration. Colipase stimulated mPLRP2 activity 2- to 4-fold. Additionally, mPTL absolutely required colipase for absorption to a lipid interface, whereas mPLRP2 absorbed fully without colipase. mPLRP2 had full activity in the presence of BSA, whereas BSA completely inhibited mPTL unless colipase was present. All of these properties of mPLRP2 differ from the properties of human PLRP2 (hPLRP2). Furthermore, mPLRP2 appears capable of compensating for mPTL deficiency. These findings suggest that the molecular mechanisms of dietary fat digestion may be different in humans and mice. Thus, extrapolation of dietary fat digestion in mice to humans should be done with care.

Molecular Characterization of the NPC1L1 Variants Identified from Cholesterol Low Absorbers

Niemann-Pick C1-like 1 (NPC1L1) is an essential protein for dietary cholesterol absorption. Nonsynonymous (NS) variants of NPC1L1 in humans have been suggested to associate with cholesterol absorption variations. However, information concerning the characteristics and mechanism of these variants in cholesterol uptake is limited. In this study, we analyzed the cholesterol uptake ability of the 19 reported NS variants of NPC1L1 identified from cholesterol low absorbers. Among these variants, L110F, R306C, A395V, G402S, T413M, R693C, R1214H, and R1268H could partially mediate cellular cholesterol uptake and were categorized as partially dysfunctional variants. The other 11 variants including T61M, N132S, D398G, R417W, G434R, T499M, S620C, I647N, G672R, S881L, and R1108W could barely facilitate cholesterol uptake, and were classified into the severely dysfunctional group. The partially dysfunctional variants showed mild defects in one or multiple aspects of cholesterol-regulated recycling, subcellular localization, glycosylation, and protein stability. The severely dysfunctional ones displayed remarkable defects in all these aspects and were rapidly degraded through the ER-associated degradation (ERAD) pathway. In vivo analyses using adenovirus-mediated expression in mouse liver confirmed that the S881L variant failed to localize to liver canalicular membrane, and the mice showed defects in biliary cholesterol re-absorption, while the G402S variant appeared to be similar to wild-type NPC1L1 in mouse liver. This study suggests that the dysfunction of the 19 variants on cholesterol absorption is due to the impairment of recycling, subcellular localization, glycosylation, or stability of NPC1L1.

The IMPROVE-IT trial: current status and potential clinical implications of ezetimibe

Reduction in low-density lipoprotein cholesterol (LDL-C) decreases the burden of coronary artery disease. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) improve cardiovascular disease outcomes by reduction of LDL-C and are currently considered first-line therapy for patients with hypercholesterolemia. Recent evidence has resulted in current guidelines recommending a more aggressive approach, with lower LDL-C goals in high-risk patients. However, despite high doses of statin therapy, targets are not met in all patients. Ezetimibe reduces cholesterol levels, in particular LDL-C, by inhibiting the intestinal absorption of both biliary and dietary cholesterol. When combined with a statin, LDL-C levels are further decreased. Ezetimibe is therefore an attractive adjunct agent to statin therapy when LDL-C targets are not achieved, yet its clinical benefits on cardiovascular outcomes await additional clinical trials. The Improved Reduction of Outcomes: Vytorin Efficacy International Tria...

Antihyperlipidemic effect of Trichilia connaroides in hypercholesterolemic rats and its possible mechanism

Objectives:The primary objective of this study was to investigate the antihyperlipidemic effect of the chloroform (CETC) and methanol (METC) extracts of leaves of Trichilia connaroides in hypercholesterolemic rats and, subsequently, to evaluate the possible mechanism of its antihyperlipidemic effect.Materials and Methods:The antihyperlipidemic activity of CETC and METC (100 mg/kg) in hypercholesterolemic rats was investigated by recording the serum lipid profile after a month-long oral treatment of these extracts. Further, hypercholesterolemic regression test and hypercholesterolemic progression test were carried out to understand the possible mechanism of its antihypercholesterolemic effect. The data were analyzed for statistical significance by one-way ANOVA, followed by Dunnet's test.Results and Conclusion:Hypercholesterolemic rats treated with CETC and METC produced a significant fall (P<0.05) in plasma triglyceride, total cholesterol, very low density lipoprotein (VLDL )-cholesterol and low density lipoprotein (LDL)-cholesterol and rise (P < 0.05) in high density lipoprotein (HDL) -cholesterol. A significant reduction (P < 0.01) in atherogenic index, increase (P < 0.05) in body weight and an insignificant influence on food intake were also observed at the end of the study. A hypercholesterolemic regression test revealed a significant reduction (P < 0.05) in the serum cholesterol level in both CETC and METC extract-treated animals. During the hypercholesterolemic progression test, a similar reduction in the serum cholesterol level was observed only in the METC extract-treated animals. The antihyperlipidemic effect was similar to fenofibrate and ezitimibe. Significant changes in the lipid profile in hypercholesterolemic animals confirm a potential antihyperlipidemic activity of the extracts. The CETC and METC extracts influenced the absorption and metabolism of dietary cholesterol to elicit the antihyperlipidemic effect.

Ezetimibe and Vascular Endothelial Function

Hypercholesterolemia is a major risk factor for cardiovascular diseases that has been managed mostly with 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (statins) that suppress de novo cholesterol synthesis in the liver. Statins also have beneficial pleiotropic effects on the atherosclerotic process that are independent of their ability to lower lipid values. However, the levels of low-density lipoprotein cholesterol (LDL-C) in most hypercholesterolemic patients at high risk for cardiovascular disease do not reach the goals proposed by guidelines even when prescribed with statins. Ezetimibe is a new lipid-lowering agent that blocks the intestinal absorption of dietary and biliary cholesterol and reduces LDL-C levels, especially when combined with statins. However, its effect on cardiovascular events remains unknown. We reviewed the effects of ezetimibe on cardiovascular diseases, in particular, vascular endothelial function, which is initially impaired during the atherogenetic process and is an important predictor of cardiovascular events. The simultaneous inhibition of cholesterol synthesis by statin and of cholesterol absorption by ezetimibe might retard the atherogenetic process. These effects are considered to be mainly mediated by lipid lowering. However, further studies should elucidate the mechanism of the anti-atherosclerotic effects induced by ezetimibe; for instance, whether or not it directly affects atherogenesis independently from its lipid-lowering effects.

Efficacy of ezetimibe as monotherapy or combination therapy in hypercholesterolemic patients with and without diabetes

Ezetimibe selectively inhibits dietary and biliary cholesterol absorption and reduces serum cholesterol levels when administered alone (monotherapy) and along with common lipid-regulating agents (combination therapy). To evaluate the effect of ezetimibe therapy on the lipid profile, glucose metabolism, and levels of cholesterol absorption and synthesis markers, we administered 10 mg ezetimibe to 50 hypercholesterolemic patients with or without diabetes. The serum levels of low-density lipoprotein cholesterol and total cholesterol were significantly reduced at 4 and 12 weeks of ezetimibe therapy in diabetic patients of both the monotherapy and combination-therapy groups and in nondiabetic patients of the combination-therapy group. The serum levels of the cholesterol absorption markers were significantly reduced, while those of the cholesterol synthesis markers were significantly increased at 12 weeks of ezetimibe therapy. No significant differences were noted in the values of the parameters of glucose metabolism in all patients. We also investigated the clinical characteristics of patients who exhibited a good response to ezetimibe (ezetimibe responders); however, multivariate regression analysis did not reveal a correlation between ezetimibe efficacy and patient characteristics such as gender, age, BMI, diabetic condition, method of ezetimibe administration, and the initial absolute values of cholesterol absorption/synthesis markers levels. In conclusion, ezetimibe therapy significantly improved the lipid profile without disturbing glucose metabolism. We were unable to identify the specific characteristics of ezetimibe responders among our subjects. However, we may interpret this result as suggesting that ezetimibe can be used in any population to lower low-density lipoprotein cholesterol levels.

Induction of microsomal triglyceride transfer protein expression is a candidate mechanism by which ezetimibe therapy might exert beneficial effects in patients with nonalcoholic steatohepatitis

Dear Editor Park and colleagues have reported that ezetimibe therapy improves the histological abnormalities of nonalcoholic fatty liver disease (NAFLD) [1]. In their study, while no significant difference was observed in the fibrosis stage, significant improvements of the steatosis grade, necroinflammatory grade, ballooning score, and NAFLD activity score (NAS) were observed after treatment with ezetimibe (10 mg/day) for 24 months. Ezetimibe, a potent inhibitor of cholesterol absorption, has been shown to inhibit Niemann-Pick C1 Like 1 (NPC1L1)-dependent cholesterol transport at the brush border of the intestine and the liver [2]. Therefore, ezetimibe has been considered as a noteworthy candidate agent for the treatment of metabolic syndrome, including nonalcoholic steatohepatitis (NASH). In several experimental rodent models, drugs antagonizing mechanisms such as sterol regulatory element-binding protein-1c (SREBP-1c) induction, carbohydrate responsive binding protein (ChREBP) induction, and endoplasmic reticulum (ER) stress have been reported as candidate mechanisms for the improvement of hepatic steatosis [3, 4]. However, unlike in rodents, in which NPC1L1 is mainly expressed in the intestine, in humans high levels of expression of NPC1L1 mRNA are observed in both the small intestine and the liver; therefore, ezetimibe would inhibit not only dietary and biliary cholesterol absorption in the small intestine, but also biliary cholesterol absorption in the liver [2]. Therefore, the mechanism by which ezetimibe might improve the changes of NASH in humans remains unknown. We conducted a 6-month pilot study to investigate the effect of ezetimibe in patients with NASH [5]. To investigate the mechanism of action of ezetimibe treatment in human NASH patients, we analyzed the hepatic mRNA expression of SREBP1c, ChREBP, and ER stress in 8 NASH patients before and after ezetimibe treatment. We found no significant changes in SREBP1c expression, ChREBP expression, or ER stress (Glucose-regulated protein 78, C/EBP-homologous protein) in this study. Secondly, we examined microsomal triglyceride transfer protein (MTTP) expression, which is a key factor for triglyceride (TG) transport in the liver, because we had previously found that the hepatic expression of MTTP mRNA was impaired in NASH patients as compared with that in patients with simple steatosis [6]. After ezetimibe treatment, a significant increase of hepatic MTTP mRNA expression was observed as compared with that before ezetimibe treatment (p = 0.0052). We suggest, therefore, that the induction of MTTP expression is an important candidate mechanism by which ezetimibe therapy might exert beneficial effects against NAFLD in humans.

Dietary cholesterol induces trafficking of intestinal Niemann-Pick Type C1 Like 1 from the brush border to endosomes

The transmembrane protein Niemann-Pick C1 Like 1 (NPC1L1) belongs to the Niemann-Pick C1 (NPC1) family of cholesterol transporters and is mainly expressed in the liver and the small intestine. NPC1L1 is believed to be the main transporter responsible for the absorption of dietary cholesterol. Like NPC1, NPC1L1 contains a sterol sensing domain, suggesting that it might be sensitive to dietary cholesterol. To test this hypothesis, mucosal explants were cultured in the presence or absence of cholesterol. In the absence of cholesterol NPC1L1 was localized mainly in the brush border of the enterocyte, colocalizing with the brush border enzyme aminopeptidase N (APN), and only a minor part was present in intracellular compartments. In contrast, following culture in the presence of cholesterol a major part of NPC1L1 was found in intracellular compartments positive for the early endosomal marker early endosome antigen 1, whereas only a minor fraction was left in the brush border. Neither APN, lactase, nor sucrase-isomaltase was endocytosed in parallel, demonstrating that this is a selective cholesterol-induced endocytosis of NPC1L1. Conceivably either the induced internalization could be due to NPC1L1 acting as an endocytic cholesterol receptor or it could be a mechanism to reduce the cholesterol uptake. The fluorescent cholesterol analog NBD-cholesterol readily labeled the cytoplasm also under conditions nonpermissible for endocytosis, arguing against a receptor-mediated uptake. We therefore propose that cholesterol is absorbed by NPC1L1 acting as a membrane transporter and that NPC1L1 is internalized to an endosomal compartment to reduce the absorption of cholesterol.

Niemann-Pick C1-Like 1 deletion in mice prevents high-fat diet-induced fatty liver by reducing lipogenesis

Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal absorption of dietary and biliary cholesterol. Ezetimibe, by inhibiting NPC1L1 function, is widely used to treat hypercholesterolemia in humans. Interestingly, ezetimibe treatment appears to attenuate hepatic steatosis in rodents and humans without a defined mechanism. Over-consumption of a high-fat diet (HFD) represents a major cause of metabolic disorders including fatty liver. To determine whether and how NPC1L1 deficiency prevents HFD-induced hepatic steatosis, in this study, we fed NPC1L1 knockout (L1-KO) mice and their wild-type (WT) controls an HFD, and found that 24 weeks of HFD feeding causes no fatty liver in L1-KO mice. Hepatic fatty acid synthesis and levels of mRNAs for lipogenic genes are substantially reduced but hepatic lipoprotein-triglyceride production, fatty acid oxidation, and triglyceride hydrolysis remain unaltered in L1-KO versus WT mice. Strikingly, L1-KO mice are completely protected against HFD-induced hyperinsulinemia under both fed and fasted states and during glucose challenge. Despite similar glucose tolerance, L1-KO relative WT mice are more insulin sensitive and in the overnight-fasted state display significantly lower plasma glucose concentrations. In conclusion, NPC1L1 deficiency in mice prevents HFD-induced fatty liver by reducing hepatic lipogenesis, at least in part, through attenuating HFD-induced insulin resistance, a state known to drive hepatic lipogenesis through elevated circulating insulin levels.

Role of Ezetimibe in the Prevention of Cardiovascular Disease: Absence of Evidence

Ezetimibe is a lipid-lowering agent that inhibits intestinal absorption of dietary cholesterol. It substantially lowers low-density lipoprotein cholesterol levels when used alone or in combination with statins. Although there is a growing push for the continued use of ezetimibe for the prevention of cardiovascular disease, ezetimibe studies available so far are inconsistent, without allowing use of the drug with confidence.

Update on the efficacy and safety of combination ezetimibe plus statin therapy

The primary aim of lipid-related cardiovascular disease (CVD) risk management is the lowering of LDL-C levels. Numerous studies have shown that statins, which inhibit cholesterol biosynthesis, effectively reduce serum LDL-C and subsequent CVD risk. Ezetimibe is an LDL-C-lowering drug that inhibits the absorption of dietary and biliary cholesterol through its interaction with the intestinal Niemann–Pick C1-like 1 sterol transporter. When combined with statin therapy, the complementary inhibition of cholesterol absorption and synthesis with these two agents is highly effective in not only reducing LDL-C, but also in improving serum levels of other lipid fractions and reducing high-sensitivity C-reactive protein levels compared with either agent alone. This article summarizes the most current clinical data available on the lipid-altering efficacy and safety of ezetimibe coadministered with statins in patients with hypercholesterolemia and in other diverse populations. In addition, the impact of ezetimibe on ...

Dietary cholesterol reverses resistance to diet-induced weight gain in mice lacking Niemann-Pick C1-Like 1

Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal cholesterol absorption. NPC1L1 knockout (L1-KO) mice were recently shown to be resistant to high-fat diet (HFD)-induced obesity in one study, which was contrary to several other studies. Careful comparison of dietary compositions in these studies implies a potential role of dietary cholesterol in regulating weight gain. To examine this potential, wild-type (WT) and L1-KO mice were fed one of three sets of diets for various durations: (1) a HFD without added cholesterol for 5 weeks; (2) a high-carbohydrate diet with or without added cholesterol for 5 weeks; or (3) a synthetic HFD with or without added cholesterol for 18 weeks. We found that L1-KO mice were protected against diet-induced weight gain only on a diet without added cholesterol but not on a diet containing 0.16% or 0.2% (w/w) cholesterol, an amount similar to a typical Western diet, regardless of the major energy source of the diet. Food intake and intestinal fat absorption were similar between the two genotypes. Intestinal cholesterol absorption was blocked, and fecal cholesterol excretion increased in L1-KO mice. Under all diets, L1-KO mice were protected from hepatosteatosis. In conclusion, increasing dietary cholesterol restores diet-induced weight gain in mice deficient in NPC1L1-dependent cholesterol absorption.