Atherosclerosis, the main contributor to coronary heart disease, is characterised by an accumulation of lipids such as cholesterol in the arterial wall. Reverse cholesterol transport (RCT) reduces cholesterol via its conversion into bile acids (BAs). During RCT in non-hepatic peripheral tissues, cholesterol is transferred to high-density lipoprotein (HDL) particles and returned to the liver for conversion into BAs predominantly via the rate-limiting enzyme, cholesterol 7 α-hydroxylase (CYP7A1). Numerous reports have described that polyphenol induced increases in BA excretion and corresponding reductions in total and LDL cholesterol in animal and in-vitro studies, but the process whereby this occurs has not been extensively reviewed. There are three main mechanisms by which BA excretion can be augmented: (1) increased expression of CYP7A1; (2) reduced expression of intestinal BA transporters; and (3) changes in the gut microbiota. Here we summarise the BA metabolic pathways focusing on CYP7A1, how its gene is regulated via transcription factors, diurnal rhythms, and microRNAs. Importantly, we will address the following questions: (1) Can polyphenols enhance BA secretion by modulating the CYP7A1 biosynthetic pathway? (2) Can polyphenols alter the BA pool via changes in the gut microbiota? (3) Which polyphenols are the most promising candidates for future research? We conclude that while in rodents some polyphenols induce CYP7A1 expression predominantly by the LXRα pathway, in human cells, this may occur through FXR, NF-KB, and ERK signalling. Additionally, gut microbiota is important for the de-conjugation and excretion of BAs. Puerarin, resveratrol, and quercetin are promising candidates for further research in this area.

https://www.mdpi.com/2072-6643/11/11/2588/pdf

Polyphenol Effects on Cholesterol Metabolism via Bile Acid Biosynthesis, CYP7A1: A Review.

Naringin and naringin's aglycone naringenin belong to a subclass of flavonoids called flavanones. While many studies of pure naringenin and naringin and their food sources have shown beneficial health effects, including improved lipid metabolism, in animals and humans, the mechanisms underlying the lipid-lowering effects are not completely understood. In recent years, multiple studies using various in vitro and rodent models have revealed new mechanisms underlying the hypolipidemic effects of naringin and naringenin, including regulation of lipid digestion, reverse cholesterol transport, and low-density lipoprotein receptor expression. In addition, naringin and naringenin show diverse effects in populations with different health conditions, such as obesity and diabetes. Furthermore, a novel naringin and naringenin enriched food source citrus bergamia (bergamot) and other citrus fruits have recently been studied for lipid-lowering effects in animal models and human clinical trials. In this review, we provide an update on recent advances in naringin and naringenin and their enriched food sources on lipid metabolism and underlying mechanisms. Because absorption, distribution, metabolism, and excretion, particularly in the presence of food matrix, impact the bioavailability, which in turn affects the bioactivities of these flavonoids in vivo, we also summarize new findings from the pharmacokinetics studies andthe interplays between the flavanones and gut microbiota. 

Beneficial Effects of Citrus Flavanones Naringin and Naringenin and Their Food Sources on Lipid Metabolism: An Update on Bioavailability, Pharmacokinetics, and Mechanisms.

In this article the Proteasome, Endoplasmic Reticulum and Mitochondria (PERM) hypothesis is discussed. The complex machinery made by three homeostatic mechanisms involving the proteasome (P), endoplasmic reticulum (ER) and mitochondria (M) is addressed in order to elucidate the beneficial role of many xenobiotics, either trace metals or phytochemicals, which are spread in the human environment and in dietary habits, exerting their actions on the mechanisms underlying cell survival (apoptosis, cell cycle regulation, DNA repair and turnover, autophagy) and stress response. The “PERM hypothesis” suggests that xenobiotics can modulate this central signaling and the regulatory engine made fundamentally by the ER, mitochondria and proteasome, together with other ancillary components such as peroxisomes, by acting on the energetic balance, redox system and macromolecule turnover. In this context, reactive species and stressors are fundamentally signalling molecules that could act as negative-modulating signals if PERM-mediated control is offline, impaired or dysregulated, as occurs in metabolic syndrome, degenerative disorders, chronic inflammation and cancer. Calcium is an important oscillatory input of this regulation and, in this hypothesis, it might play a role in maintaining the correct rhythm of this PERM modulation, probably chaotic in its nature, and guiding cells to a more drastic decision, such as apoptosis. The commonest effort sustained by cells is to maintain their survival balance and the proterome has the fundamental task of supporting this mechanism. Mild stress is probably the main stimulus in this sense. Hormesis is therefore re-interpreted in the light of this hypothetical model and that experimental evidence arising from flavonoid and hormesis reasearch.

PERM Hypothesis: The Fundamental Machinery Able to Elucidate the Role of Xenobiotics and Hormesis in Cell Survival and Homeostasis

Methotrexate (MTX) is an efficient chemotherapeutic and immunosuppressant drug, but the hepatotoxicity of MTX limits its clinical use. Naringin (Nar) is a flavonoid derived from Citrus paradise, and has been shown to possess several pharmacological activities, including free-radical scavenging and antioxidant properties. In the present study, we first tested the possible protective effects of multiple doses of Nar against MTX-induced acute hepatotoxicity in rats, and then we investigated the growth inhibition and apoptotic effects of MTX and/or Nar against the HepG2 hepatocarcinoma cell line. Our in vivo results showed that Nar significantly reduced MTX-induced increases in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin levels. Nar also reduced MTX-induced oxidative stress by significantly reducing liver malondialdehyde (MDA) and nitric oxide (NO) content and increasing superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH). In addition, Nar significantly counteracted MTX-induced increases in hepatic interleukin-6 and tumor necrosis factor-α (TNF-α). Further, Nar greatly protected hepatocyte ultrastructure against MTX-induced injury. In contrast, in vitro MTX and/or Nar treatment of HepG2 cells for 48 h exhibited a cytotoxic effect and induced apoptosis in a dose-dependent manner mediated by a significant increase in the Bax/Bcl-2 protein expression ratio. Noticeably, Nar potentiated the MTX effect on the Bax/Bcl-2 ratio. In conclusion, Nar decreased MTX-induced functional and ultrastructural liver damage in a tumor-free animal model. Also, our data introduce MTX and Nar as promising antiproliferative agents with a distinctive mode of action, inducing apoptosis in HepG2 tumor cells through activation of Bax and down-regulation of Bcl-2 protein expression.

/pdf/naringin-alleviates-methotrexate-induced-liver-injury-in-44fksykrlo.pdf

Naringin alleviates methotrexate-induced liver injury in male albino rats and enhances its antitumor efficacy in HepG2 cells

Naringin is a plant flavonoid of huge medicinal importance. It is synthesized by the phenylpropanoid pathway via seven enzyme catalysed steps from phenylalanine to prunin. The genes encoding the enzymes of phenylpropanoid pathway have been cloned and characterized. Naringin has been known to possess antioxidant, antiinflammatory and antitumer potential. Exposure to naringin in vivo and in vitro in several test animals and cell lines has been reported to demonstrate activities that could treat asthma, hyperlipidemia, diabtetes, tumor, hyperthyroidism and osteoclastogenesis. Based on the reported research of naringin on test animals, naringin could be regarded as an efficient natural remedy for the treatment of human metabolic disorders. However, detailed exploration of naringin exposure on humans needs to be studied.

/pdf/naringin-biosynthesis-and-pharmaceutical-applications-2th9ex8xre.pdf

Naringin: Biosynthesis and Pharmaceutical Applications

The main purpose of this study was to examine if naringin contributed to the regulation of cholesterol homeostasis and inflammatory cytokine expressions in cholesterol and 25-OH-cholesterol-treated HepG2 cells and TNF-α-treated HUVECs. The gene and protein expressions related to cholesterol homeostasis and inflammation were determined by quantitative real-time reverse transcription-polymerase chain reaction and Western blotting. We obtained the following results: (1) A concentration-dependent increase of LDLR and CYP7A1 expressions was observed, through activating expressions of SREBP2 and PPARy in HepG2 cells after exposure to naringin; (2) EL gene and protein expressions in HUVECs were inhibited by naringin; (3) the expressions of inflammatory factors such as CRP, TNF-α, ICAM-1 and VCAM-1 in HepG2 cells, ICAM-1 and VCAM-1 in HUVECs restrained by naringin were confirmed; (4) NF-κB and ERK1/2 activities were quenched by naringin. In summary, naringin might not only effectively reduce cholesterol levels by stimulating cholesterol metabolism but also inhibit inflammatory response through reducing inflammatory cytokine expressions. The effects of naringin were achieved via modulating NF-κB and ERK signaling pathways.

Naringin regulates cholesterol homeostasis and inhibits inflammation via modulating NF-κB and ERK signaling pathways in vitro.

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Naringin regulates cholesterol homeostasis and inhibits inflammation via modulating NF-κB and ERK signaling pathways in vitro.