phytosterols and Non-alcoholic-Fatty-Liver-Disease

Phytosterols are bioactive food components widely present in cell membranes of plants, especially in nuts and oilseeds. In recent years, many studies have shown that phytosterols possess therapeutic potentials for nonalcoholic fatty liver disease (NAFLD). This review summarizes the effects of phytosterols from in vitro and in vivo studies to lower the levels of total cholesterol (TC) and triglycerides (TG), and the evidence supporting the potential of phytosterols against NAFLD. The potential mechanisms by which phytosterols improve NAFLD may include (i) competition with cholesterol; (ii) regulation of key factors involved in cholesterol and TG metabolism; and (iii) inhibition of liver inflammation and (iv) regulation of liver fatty acid composition. In summary, phytosterols are potential natural ingredients with good safety profile against NAFLD, which deserve more future studies.

Topics: Cholesterol; Humans; Liver; Non-alcoholic Fatty Liver Disease; Phytosterols; Triglycerides

Nonalcoholic fatty liver disease is now recognized as the most common cause of chronic liver disease with an increasing prevalence in both adults and children. Although the symptoms are absent or poorly expressed in most cases, some patients may progress to end-stage liver disease. The pathogenesis of NAFLD is known to be multifactorial. Current therapeutic recommendations focus on lifestyle changes in order to reduce the incidence of risk factors and drugs targeting major molecular pathways potentially involved in the development of this disease. Given that a pharmacological treatment, completely safe and effective, is not currently known in recent years more research has been done on the effects that some bio-active natural compounds, derived from plants, have in preventing the onset and progression of NAFLD. Numerous studies, in animals and humans, have shown that phytosterols (PSs) play an important role in this pathology. Phytosterols are natural products that are found naturally in plant. More than 250 phytosterols have been identified, but the most common in the diet are stigmasterol, β-sitosterol, and campesterol. Consumption of dietary PSs can reduce serum cholesterol levels. Due to these properties, most studies have focused on their action on lipid metabolism and the evolution of NAFLD. PSs may reduce steatosis, cytotoxicity oxidative stress, inflammation, and apoptosis. The purpose of this review is to provide an overview of the importance of dietary phytosterols, which are a window of opportunity in the therapeutic management of NAFLD.

Topics: Animals; Diet; Humans; Lipid Metabolism; Non-alcoholic Fatty Liver Disease; Phytosterols; Stigmasterol

Consumption of phytosterols (PSs), the plant-based analogs of cholesterol, can reduce serum cholesterol levels. This review discusses the current state of the art into the research of the structural features and dietary sources of PSs and their derivatives. The effect of PSs on individual lipid metabolites is summarized in the present review. PS-related nonalcoholic fatty liver disease (NAFLD), obesity, and the alleviation of inflammatory bowel diseases are discussed. PSs reduce the risk of having NAFLD by improving the blood biochemical parameters related to lipid transport and metabolism. However, current research on the circulating PSs indicates its safety concern regarding fatty liver disease induction. In addition, PS oxidation products exhibit pro-atherogenic properties, cytotoxicity oxidative stress, apoptosis, and pro-inflammatory properties. Further research is needed to investigate the bioavailability and safety issues of PSs and their derivatives in animal models and clinical trials.

Topics: Animals; Anticholesteremic Agents; Cholesterol; Diet; Humans; Inflammatory Bowel Diseases; Lipid Metabolism; Non-alcoholic Fatty Liver Disease; Obesity; Oxidation-Reduction; Phytosterols

Liver ailments are among the leading causes of death; they originate from viral infections, chronic alcoholism, and autoimmune illnesses, which may chronically be precursors of cirrhosis; furthermore, metabolic syndrome may worsen those hepatopathies or cause Non-alcoholic Fatty Liver Disease (NAFLD) that may advance to non-alcoholic steatohepatitis (NASH). Cirrhosis is the late-stage liver disease and can proceed to hepatocellular carcinoma (HCC). Pharmacological treatment options for liver diseases, cirrhosis, and HCC, are limited, expensive, and not wholly effective. The use of medicinal herbs and functional foods is growing around the world as natural resources of bioactive compounds that would set the basis for the development of new drugs.. Plant and food-derived sterols and triterpenoids (TTP) possess antioxidant, metabolic-regulating, immunomodulatory, and anti-inflammatory activities, as well as they are recognized as anticancer agents, suggesting their application strongly as an alternative therapy in some chronic diseases. Thus, it is interesting to review current reports about them as hepatoprotective agents, but also because they structurally resemble cholesterol, sexual hormones, corticosteroids and bile acids due to the presence of the steroid nucleus, so they all can share pharmacological properties through activating nuclear and membrane receptors. Therefore, sterols and TTP appear as a feasible option for the prevention and treatment of chronic metabolic-related liver diseases, cirrhosis, and HCC.

Topics: Animals; Antioxidants; Carcinoma, Hepatocellular; Humans; Liver; Liver Cirrhosis; Liver Neoplasms; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Phytosterols; Triterpenes

Dietary plant sterols and stanols as present in our diet and in functional foods are well-known for their inhibitory effects on intestinal cholesterol absorption, which translates into lower low-density lipoprotein cholesterol concentrations. However, emerging evidence suggests that plant sterols and stanols have numerous additional health effects, which are largely unnoticed in the current scientific literature. Therefore, in this review we pose the intriguing question "What would have occurred if plant sterols and stanols had been discovered and embraced by disciplines such as immunology, hepatology, pulmonology or gastroenterology before being positioned as cholesterol-lowering molecules?" What would then have been the main benefits and fields of application of plant sterols and stanols today? We here discuss potential effects ranging from its presence and function intrauterine and in breast milk towards a potential role in the development of non-alcoholic steatohepatitis (NASH), cardiovascular disease (CVD), inflammatory bowel diseases (IBD) and allergic asthma. Interestingly, effects clearly depend on the route of entrance as observed in intestinal-failure associated liver disease (IFALD) during parenteral nutrition regimens. It is only until recently that effects beyond lowering of cholesterol concentrations are being explored systematically. Thus, there is a clear need to understand the full health effects of plant sterols and stanols.

Topics: Asthma; Cardiovascular Diseases; Cholesterol; Cholesterol, LDL; Humans; Inflammatory Bowel Diseases; Intestinal Absorption; Non-alcoholic Fatty Liver Disease; Phytosterols; Sitosterols

The aim of this study was to investigate the combined effect of n-3 fatty acids (EPA and DHA, at an EPA:DHA ratio of 150:500) and phytosterol esters (PS) on non-alcoholic fatty liver disease (NAFLD) patients. We conducted a randomised, double-blind, placebo-controlled trial. Ninety-six NAFLD subjects were randomly assigned to the following groups: the PS group (receiving 3·3 g/d PS); the FO group (receiving 450 mg EPA + 1500 mg DHA/d); the PS + FO combination group (receiving 3·3 g/d PS and 450 mg EPA + 1500 mg DHA/d) and the PO group (a placebo group). The baseline clinical characteristics of the four groups were similar. The primary outcome was liver:spleen attenuation ratio (L:S ratio). The percentage increase in liver-spleen attenuation (≤1) in the PS + FO group was 36 % (P = 0·083), higher than those in the other three groups (PS group, 11 %, P = 0·519; FO group, 18 %, P = 0·071; PO group, 15 %, P = 0·436). Compared with baseline, transforming growth factor-β (TGF-β) was significantly decreased in the three study groups at the end of the trial (PS, P = 0·000; FO, P = 0·002; PS + FO, P = 0·001) and TNF-α was significantly decreased in the FO group (P = 0·036), PS + FO group (P = 0·005) and PO group (P = 0·032) at the end of the intervention. Notably, TGF-β was reduced significantly more in the PS + FO group than in the PO group (P = 0·032). The TAG and total cholesterol levels of the PS + FO group were reduced by 11·57 and 9·55 %, respectively. In conclusion, co-supplementation of PS and EPA + DHA could increase the effectiveness of treatment for hepatic steatosis.

Topics: Adult; Dietary Supplements; Double-Blind Method; Esters; Fatty Acids, Omega-3; Female; Humans; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Phytosterols; Spleen; Treatment Outcome

Increasing evidence demonstrated that pyroptosis and subsequent inflammation played an important role in the pathological process of non-alcoholic steatohepatitis (NASH). Plant sterol ester of α-linolenic acid (PS-ALA) was beneficial for non-alcoholic fatty liver disease, but the underlying mechanisms are still not fully understood. This study aims to investigate whether PS-ALA can protect against proptosis via regulating SIRT1. Thirty male C57BL/6J mice were fed a normal diet, a high-fat and high-cholesterol diet (HFCD), or a HFCD supplemented with either 1.3%ALA, 2%PS, or 3.3% PS-ALA for 24 weeks. Hepatocytes were treated with oleic acid and cholesterol (OA/Cho) with or without PS-ALA. We found that PS-ALA ameliorated NASH in HFCD-fed mice. In addition, PS-ALA decreased the expression of NLRP3 and ASC and reduced the co-localization of NLRP3 and cleave-Caspase-1. Also, PS-ALA protected against pyroptosis as evidenced by decreased co-localization of GSDMD and propidium iodide (PI) positive cells. Mechanistically, we revealed that the inhibitory action of PS-ALA on the pyroptosis was mediated by SIRT1. This was demonstrated by the fact that silencing SIRT1 with small interfering RNA or inhibition of SIRT1 with its inhibitor abolished the inhibition effect of PS-ALA on the expression of NLRP3 and GSDMD cleavage. Collectively, the data from the present study reveals a novel mechanism that PS-ALA inhibits pyroptosis and it triggered inflammation via stimulating SIRT1, which provides new insights into the beneficial effect of PS-ALA on NASH.

Topics: alpha-Linolenic Acid; Animals; Cholesterol; Esters; Inflammation; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Non-alcoholic Fatty Liver Disease; Phytosterols; Pyroptosis; Sirtuin 1

Apoptosis is a feature of progressions steatosis to nonalcoholic steatohepatitis (NASH) and can be explained by endoplasmic reticulum stress (ERS). The present study aimed to investigate the protective effects of plant sterol ester of α-linolenic acid (PS-ALA) on ERS-triggered apoptosis in high fat diet-fed mice and oleic acid-induced hepatocytes, and further explore the underlying mechanisms. Our results showed that PS-ALA improved Non-alcoholic fatty liver disease (NAFLD) in both in vivo and in vitro models. Moreover, PS-ALA treatment can attenuate ERS and associated apoptosis via inhibiting IRE1α/TRAF2/JNK signal pathway. Furthermore, we found that the protective effect of PS-ALA on ERS-triggered apoptosis was mediated by activation of AMP-activated protein kinase (AMPK) as pretreatment with Compound C, an AMPK inhibitor, abolished the anti-apoptotic effect of PS-ALA. Taken together, our results illustrate that PS-ALA attenuating ERS-mediated apoptosis via activating AMPK, which provided new insights into the protective effect of PS-ALA in NAFLD.

Topics: alpha-Linolenic Acid; AMP-Activated Protein Kinases; Animals; Apoptosis; Endoplasmic Reticulum Stress; Endoribonucleases; Esters; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Phytosterols; Protein Serine-Threonine Kinases

The present study was designed to explore the beneficial mitochondrial effects and anti-oxidative activities of plant sterol ester of α-linolenic acid (PS-ALA) through AMP-activated protein kinase (AMPK) signaling in the treatment of nonalcoholic fatty liver disease (NAFLD) using in vivo and in vitro models. The mitochondrial function was evaluated and the oxidative stress index was measured. The protein expression was analyzed by immunohistochemical, immunofluorescence, and western blotting methods. The results showed that PS-ALA significantly suppressed NAFLD and alleviated steatosis in HepG2 cells induced by oleic acid (OA). In addition, PS-ALA promoted mitochondrial biogenesis, enhanced mitochondrial fatty acid oxidation capacity, improved mitochondrial dynamics, and restored mitochondrial membrane potential. Moreover, PS-ALA reduced reactive oxygen species production both in the liver tissue of HFD-fed mice and OA-loaded HepG2 cells. At the molecular level, PS-ALA accelerated the phosphorylation of AMPK and increased the protein expression of peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) and nuclear NF-E2-related factor 2 (Nrf2). Furthermore, the stimulating effects of PS-ALA on the PGC-1α/Nrf1/Tfam pathway and Nrf2/HO-1 pathway as well as its mitochondrial biogenesis promotion effects and anti-oxidative activities were abrogated by the AMPK inhibitor in OA-treated HepG2 cells. In conclusion, the protective effects of PS-ALA on NAFLD appear to be associated with improving mitochondrial function and oxidative stress via activating AMPK signaling.

Topics: alpha-Linolenic Acid; AMP-Activated Protein Kinases; Animals; Diet, High-Fat; Enzyme Activation; Esters; Hep G2 Cells; Humans; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondria, Liver; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phosphorylation; Phytosterols; Reactive Oxygen Species; Signal Transduction

Recent studies have shown that the occurrence and progression of nonalcoholic fatty liver disease (NAFLD) can be aggravated by dysregulation of intestinal flora. We previously found that phytosterol esters (PSEs) could effectively prevent the progression of NAFLD. Here, we further investigated the regulatory effect that PSEs have on gut flora and faecal metabolites in rats with NAFLD. Adult SD (Sprague Dawley) rats were randomized into four groups: the normal chow diet (NC), high-fat diet (HFD), low-dose PSE (0.05 g per 100 g BW, PSEL) and high-dose PSE (0.10 g per 100 g BW, PSEH) groups. PSEs were intragastrically administered once a day for 12 consecutive weeks. Our work indicated that high-dose PSE treatment effectively inhibited the increase in liver and abdominal fat indexes (P < 0.01) and hepatic lipids (P < 0.01); a high dose PSE treatment effectively corrected the HFD-induced intestinal flora imbalance by changing the diversity. The relative abundances of the four phyla (Firmicutes, Proteobacteria, Actinobacteria and Verrucomicrobia) and partial bacteria at the genus level (Faecalibacterium, Akkermansia, etc.) in the PSEH group were closer to those in the NC group. High-dose PSE intervention significantly increased the relative abundance of Bacteroidetes and Anaerostipes. Compared with the HFD, PSEH treatment significantly decreased the ionic strengths of bile acid metabolism products (P < 0.05), which were positively correlated with hepatic steatosis. In conclusion, PSE treatment exerts a beneficial effect on NAFLD that is associated with its regulatory action on intestinal flora and faecal metabolites, which might present a new opportunity to develop effective and safe preventive strategies against NAFLD.

Topics: Animals; Bacteria; Diet, High-Fat; Esters; Feces; Gastrointestinal Microbiome; Lipid Metabolism; Lipids; Male; Non-alcoholic Fatty Liver Disease; Phytosterols; Rats; Rats, Sprague-Dawley

Both serum and hepatic fatty acid (FA) compositions differ among nonalcoholic hepatic steatosis, nonalcoholic steatohepatitis, and healthy subjects. The severity of the above liver disease is closely associated with the concentration and composition of FAs. Our previous study found that phytosterol ester (PSE) could alleviate hepatic steatosis in nonalcoholic fatty liver disease rats. The aims of this work were to explore the effects of PSE (0.05/100 g·body weight) on FA profiles and the mRNA levels of FA metabolism-related genes. Compared with a high-fat diet alone group, PSE treatment significantly decreased hepatic saturated fatty acid levels (

Topics: Adipose Tissue; Animals; Diet, High-Fat; Esters; Fatty Acids, Unsaturated; Gas Chromatography-Mass Spectrometry; Liver; Male; Non-alcoholic Fatty Liver Disease; Phytosterols; Rats; Rats, Sprague-Dawley

Gallstone disease (GD) has been associated with low serum levels of plant sterols. We evaluated the impact of laparoscopic Roux-en-Y gastric bypass (LRYGB) and non-alcoholic fatty liver disease (NAFLD) on the association of GD with low levels of serum plant sterols.. Two hundred forty-two consecutive morbidly obese patients were recruited to this prospective study. Histological analysis of liver biopsy to diagnose NAFLD was performed. Bile sample was taken during the LRYGB. Associations of GD with serum non-cholesterol sterol to cholesterol ratios, measured using gas liquid chromatography and with mRNA expression of genes participating in the cholesterol, bile, and fatty acid metabolism in the liver, were analyzed.. Out of the 242 participants, 95 had GD. Lower weight (p = 0.002) and female sex (p = 0.0006) were associated with GD. Serum plant sterols, campesterol (p = 0.003), sitosterol (p = 0.002), and avenasterol (p = 0.015), were lower in patients with GD compared to those without GD. This association remained significant after adjustment for NAFLD, use of statin medication, and previous laparoscopic cholecystectomy (LCC). Levels of sitosterol (p = 0.001) and campesterol (p = 0.001) remained lower in obese individuals with GD also after obesity surgery. Liver mRNA expression of genes regulating cholesterol synthesis and bile metabolism was increased in individuals with GD.. Serum plant sterols were lower in patients with GD independent of NAFLD, history of LCC, use of statin medication, and weight loss after LRYGB. Low serum plant sterols in patients with GD suggest potentially inherited alterations in sterol absorption and biliary transport in subjects susceptible for GD.

Topics: Adult; Bile; Female; Gallstones; Gastric Bypass; Humans; Laparoscopy; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Phytosterols; Prospective Studies; Weight Loss

Various human trials and pre-clinical studies have suggested that dietary plant sterols possess hypotriacylglycerolaemic properties apart from their cholesterol-lowering properties. We hypothesised that phytosterols (PS) might attenuate triacylglycerolaemia by interfering with the deleterious effects of cholesterol overload in the liver. In the present study, twenty hamsters (Mesocricetus auratus) with diet-induced combined hyperlipidaemia were fed a high-fat diet (HFD, n 10) or a HFD supplemented with soyabean PS (n 10) for 40 d. In parallel, a healthy group was fed a standard diet (n 10). PS normalised fasting plasma cholesterol concentrations completely after 20 d and were also able to normalise serum TAG and NEFA concentrations after 40 d. HFD feeding caused microvesicular steatosis and impaired the expression of key genes related to fatty acid oxidation such as PPARA, carnitine palmitoyltransferase-Iα (CPT1A) and phosphoenolpyruvate carboxykinase 1 (PCK1) in the liver. PS treatment completely protected against HFD-induced steatosis and resulted in a normalised hepatic gene expression profile. The protection of the hepatic function by PS was paralleled by increased faecal cholesterol excretion along with a 2-fold increase in the biliary bile acid (BA):cholesterol ratio. The present study supports the conclusion that long-term consumption of PS can reduce serum TAG and NEFA concentrations and can protect against the development of fatty liver via different mechanisms, including the enhancement of BA synthesis. The results of the present study place these compounds as promising hepatoprotective agents against fatty liver and its derived pathologies.

Topics: Animals; Bile Acids and Salts; Carnitine O-Palmitoyltransferase; Cholesterol; Cricetinae; Diet, High-Fat; Dyslipidemias; Fatty Acids, Nonesterified; Fatty Liver; Gene Expression; Glycine max; Lipogenesis; Liver; Male; Mesocricetus; Non-alcoholic Fatty Liver Disease; Phosphoenolpyruvate Carboxykinase (GTP); Phytosterols; PPAR alpha; Triglycerides

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.

Topics: Animals; Cholesterol; Desmosterol; Dietary Fats; Female; Humans; Inflammation; Liver; Macrophages; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Phytosterols

We investigated how liver fat content (LFC) influences cholesterol metabolism by quantifying liver fat using proton magnetic resonance spectroscopy and by measuring the serum concentrations of lathosterol, a marker of cholesterol synthesis, and sitosterol and campesterol, two markers of cholesterol absorption. We also evaluated whether this relationship could be modified by statin therapy. The study was conducted in 263 patients with type 2 diabetes, 137 of whom (52.0%) received statin therapy.. One hundred and sixty-five patients (62.7%) had steatosis (LFC>5.5%). We performed specific analyses in patients without statin therapy and in patients treated with statin therapy. In both groups, the lathosterol to cholesterol ratio correlated positively with LFC, and in multivariate analysis, the lathosterol to cholesterol ratio was associated with LFC independently of age, gender and BMI. Sitosterol and campesterol concentrations were not associated with LFC.. Our study suggests that in patients with type 2 diabetes, LFC is associated with an increase in cholesterol synthesis that is independent of obesity or diabetes mellitus. Statin therapy does not modify this relationship.

Topics: Aged; Biomarkers; Cholesterol; Diabetes Mellitus, Type 2; Dyslipidemias; Fatty Liver; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Linear Models; Liver; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Phytosterols; Risk Factors; Sitosterols; Treatment Outcome

Topics: Diet; Diet Therapy; Fatty Liver; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Lipid Metabolism; Meta-Analysis as Topic; Non-alcoholic Fatty Liver Disease; Phytosterols; Risk Factors; Triglycerides