Going "Green" in the Prevention and Management of Atherothrombotic Diseases: The Role of Dietary Polyphenols

Abstract

During the 20th century processed and ready-to-eat foods became routinely consumed resulting in a sharp rise of fat, salt, and sugar intake in people's diets. Currently, the global incidence of obesity, raised blood lipids, hypertension, and diabetes in an increasingly aged population contributes to the rise of atherothrombotic events and cardiovascular diseases (CVD) mortality. Drug-based therapies are valuable strategies to tackle and help manage the socio-economic impact of atherothrombotic disorders though not without adverse side effects. The inclusion of fresh fruits and vegetables rich in flavonoids to human diets, as recommended by WHO offers a valuable nutritional strategy, alternative to drug-based therapies, to be explored in the prevention and management of atherothrombotic diseases at early stages. Though polyphenols are mostly associated to color and taste in foods, food flavonoids are emerging as modulators of cholesterol biosynthesis, appetite and food intake, blood pressure, platelet function, clot formation, and anti-inflammatory signaling, supporting the health-promoting effects of polyphenol-rich diets in mitigating the impact of risk factors in atherothrombotic disorders and CVD events. Here we overview the current knowledge on the effect of polyphenols particularly of flavonoid intake on the atherothrombotic risk factors and discuss the caveats and challenges involved with current experimental cell-based designs.

Keywords: CVD; appetite; gut metabolites; hypertension; inflammation; lipoproteins; mediterranean diets; obesity; vascular health.

Figure 1

Number of publications using the search string “flavonoids” with other keywords (SCOPUS database, searched 21 December 2020).

Figure 2

Intracellular and extracellular transport of cholesterol. Extracellular free cholesterol is delivered to various cells via LDL. The LDL then interacts with the LDL_R and enters the cells through endocytosis. The free cholesterol is then dissociated from the receptor in the cell lysosome and the unbound receptor is then recycled to the cell membrane for continuous removal of serum cholesterol. However, these LDL_Rs undergo lysosomal degradation in the presence of PCSK9. The cholesterol is then distributed within the cells for different functions. Intracellular cholesterol molecules are used to maintain the membrane rigidity through lipid rafts or converted to CEs by ACAT in the endoplasmic reticulum and stored as lipid droplets mediated by CETP. Furthermore, SREBP regulates intracellular cholesterol synthesis and uptake between the endoplasmic reticulum and Golgi body. Intracellular cholesterol homeostasis is maintained through ABCA1, SR-B1, LXR, and caveolins. The coupling of P-gp to ABCA1 regulates cellular toxicity by transporting cytotoxic drugs or compounds to the extracellular matrix. Therefore, ABCA1 is an important protein involved in MDR. In addition, MDR occurs when there is an increase in caveolin (red arrow), which increases membrane cholesterol. Extracellular cholesterol homeostasis is maintained by lipoproteins, HDL and LDLs. Cholesterol is then cleared through HDLs (which interact with SR-B1) to be excreted by the liver or shuttled by CETP from HDLs to the LDLs, which bind to LDL_Rs on hepatocytes for cholesterol clearance. (Reprinted with permission from Wiley & Sons from Gu L, Saha TS, Thomas J, Kaur M. “Targeting cellular cholesterol for anticancer therapy” published in FEBS J. (2019) 286, 4192–4208).