Phytosterols are natural sterols widely found in plants that have a variety of physiological functions, and their role in reducing cholesterol absorption has garnered much attention. Although the bioavailability of phytosterols is only 0.5–2%, they can still promote cholesterol balance in the body. A mechanism of phytosterols for lowering cholesterol has now been proposed. They not only reduce the uptake of cholesterol in the intestinal lumen and affect its transport, but also regulate the metabolism of cholesterol in the liver. In addition, phytosterols can significantly reduce the plasma concentration of total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C), with a dose-response relationship. Ingestion of 3 g of phytosterols per day can reach the platform period, and this dose can reduce LDL-C by about 10.7%. On the other hand, phytosterols can also activate the liver X receptor α-CPY7A1 mediated bile acids excretion pathway and accelerate the transformation and metabolism of cholesterol. This article reviews the research progress of phytosterols as a molecular regulator of cholesterol and the mechanism of action for this pharmacological effect.

S-adenosylhomocysteine (SAH) is hydrolyzed by SAH hydrolase (SAHH) to homocysteine and adenosine. Increased plasma SAH levels were associated with disturbed renal function in patients with diabetes. However, the role and mechanism of SAHH in diabetic nephropathy is still unknown. In the present study, we found that inhibition of SAHH by using its inhibitor adenosine dialdehyde (ADA) accumulates intracellular or plasma SAH levels and increases high glucose-induced podocyte injury and aggravates STZ-induced diabetic nephropathy, which is associated with Nod-like receptor protein 3 (NLRP3) inflammasome activation. Inhibition or knockout of NLRP3 attenuates SAHH inhibition-aggravated podocyte injury and diabetic nephropathy. Additionally, SAHH inhibition increases thioredoxin-interacting protein (TXNIP)-mediated oxidative stress and NLRP3 inflammasome activation, but these effects were not observed in TXNIP knockout mice. Mechanistically, SAHH inhibition increased TXNIP by inhibiting histone methyltransferase enhancer of zeste homolog 2 (EZH2) and reduced trimethylation of histone H3 lysine 27 and its enrichment at promoter of early growth response 1 (EGR1). Moreover, EGR1 is activated and enriched at promoters of TXNIP by SAHH inhibition and is essential for SAHH inhibition-induced TXNIP expression. Inhibition of EGR1 protected against SAHH inhibition-induced NLRP3 inflammasome activation and oxidative stress and diabetic nephropathy. Finally, the harmful effects of SAHH inhibition on inflammation and oxidative stress and diabetic nephropathy were also observed in heterozygote SAHH knockout mice. These findings suggest that EZH2/EGR1/TXNIP/NLRP3 signaling cascade contributes to SAHH inhibition-aggravated diabetic nephropathy. Our study firstly provides a novel insight into the role and mechanism of SAHH inhibition in diabetic nephropathy.

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease that can progress to cirrhosis and liver failure. Anthocyanin, a member of the flavonoid family, has been shown to ameliorate NAFLD-associated pathologies in rodents.The aim of this CONSORT-compliant pilot study is to evaluate the effects of anthocyanin supplementation on insulin resistance and liver injury biomarkers in patients with NAFLD.A total of 74 subjects with NAFLD were divided into 2 groups in this double-blind, randomized study. Patients received either purified anthocyanin (320 mg/d) derived from bilberry and black currant or placebo for 12 weeks. Diet, physical activity, anthropometric parameters, glucose tolerance, and a set of biomarkers related to NAFLD were evaluated before and after intervention.No significant differences were observed in nutrient intake, physical activity, anthropometric parameters, or plasma lipid profile between patients receiving anthocyanin or placebo. Compared to controls, the anthocyanin group exhibited significant decreases (P < 0.05, all comparisons) in plasma alanine aminotransferase (-19.1% vs 3.1%), cytokeratin-18 M30 fragment (-8.8% vs 5.6%) and myeloperoxidase (-75.0% vs -44.8%). Significant decreases from baseline in fasting blood glucose and homeostasis model assessment for insulin resistance were observed in the anthocyanin group; however, these differences were not significant relative to placebo controls. In addition, the oral glucose tolerance test indicated that anthocyanin supplementation significantly decreased the 2-hour loading glucose level compared to control (-18.7% vs -3.8%, P = 0.02).A 12-week supplement of purified anthocyanin improved insulin resistance, indicators of liver injury, and clinical evolution in NAFLD patients. Further studies are warranted to determine the clinical applications of anthocyanin in NAFLD.This trial was registered at clinicaltrials.gov as NCT01940263.