Targeting Mitochondria for the Prevention and Treatment of Nonalcoholic Fatty Liver Disease: Polyphenols as a Non-pharmacological Approach.

SCOPE: Nonalcoholic fatty liver disease (NAFLD) has a high and growing prevalence globally. Mitochondria are fundamental in regulating cell energy homeostasis. Nevertheless, mitochondria control mechanisms can be exceeded in this context of energy overload. Damaged mitochondria worsen NAFLD progression. Diet and lifestyle changes are the main recommendations for NAFLD prevention and treatment. Some polyphenols have improved mitochondrial function in different NAFLD and obesity models. OBJECTIVE: The study aims to discuss the potential role of polyphenols as a nonpharmacological approach targeting mitochondria to prevent and treat NAFLD, analyzing the influence of polyphenols' chemical structure, limitations and clinical projections. METHODS: In vivo and in vitro NAFLD models were considered. Study searches were performed using the following keywords: nonalcoholic fatty liver disease, liver steatosis, mitochondria, mitochondrial activity, mitochondrial dynamics, mitochondrial dysfunction, mitochondrial morphology, mitochondrial cristae, fusion, fission, polyphenols, flavonoids, anthocyanins, AND/OR bioactive compounds. CONCLUSION: Polyphenols are a group of diverse bioactive molecules whose bioactive effects are highly determined by their chemical structure. These bioactive compounds could offer an interesting non-pharmacological approach to preventing and treating NAFLD, regulating mitochondrial dynamics and function. Nevertheless, the mitochondria' role in subjects with NAFLD treatment is not fully elucidated. The dosage and bioavailability of these compounds should be addressed when studied.

The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic ß-cells, glycemic control and inflammation: In vitro and in vivo studies.

Studying rats fed high cholesterol diet and a pancreatic ß-cell line (Min6), we aimed to determine the mechanisms by which quercetin protects against cholesterol-induced pancreatic ß-cell dysfunction and impairments in glycemic control. Quercetin prevented the increase in total plasma cholesterol, but only partially prevented the high cholesterol diet-induced alterations in lipid profile. Quercetin prevented cholesterol-induced decreases in pancreatic ATP levels and mitochondrial bioenergetic dysfunction in Min6 cells, including decreases in mitochondrial membrane potentials and coupling efficiency in the mitochondrial respiration (basal and maximal oxygen consumption rate (OCR), ATP-linked OCR and reserve capacity). Quercetin protected against cholesterol-induced apoptosis of Min6 cells by inhibiting caspase-3 and -9 activation and cytochrome c release. Quercetin prevented the cholesterol-induced decrease in antioxidant defence enzymes from pancreas (cytosolic and mitochondrial homogenates) and Min6 cells and the cholesterol-induced increase of cellular and mitochondrial oxidative status and lipid peroxidation. Quercetin counteracted the cholesterol-induced activation of the NFκB pathway in the pancreas and Min6 cells, normalizing the expression of pro-inflammatory cytokines. Quercetin inhibited the cholesterol-induced decrease in sirtuin 1 expression in the pancreas and pancreatic ß-cells. Taken together, the anti-apoptotic, antioxidant and anti-inflammatory properties of quercetin, and its ability to protect and improve mitochondrial bioenergetic function are likely to contribute to its protective action against cholesterol-induced pancreatic ß-cell dysfunction, thereby preserving glucose-stimulated insulin secretion (GSIS) and glycemic control. Specifically, the improvement of ATP-linked OCR and the reserve capacity are important mechanisms for protection of quercetin. In addition, the inhibition of the NFκB pathway is an important mechanism for the protection of quercetin against cytokine mediated cholesterol-induced glycemic control impairment. In summary, our data highlight cellular, molecular and bioenergetic mechanisms underlying quercetin's protective effects on ß-cells in vitro and in vivo, and provide a scientifically tested foundation upon which quercetin can be developed as a nutraceutical to preserve ß-cell function.

Vitamin C in the treatment and/or prevention of obesity.

Obesity has emerged as one of the major health threats worldwide. Moreover, an excessive body fat accumulation, which defines this disease, could lead to several associated clinical manifestations such as cardiovascular events, type 2 diabetes, inflammation, and some types of cancer. The appearance of these co-morbidities has been often related to an unbalanced oxidative stress. Therefore, antioxidant-based treatments could be considered as interesting approaches to possibly counteract obesity fat accumulation complications. In this context, it has been observed that vitamin C intake (ascorbic acid) is negatively associated with the occurrence of several conditions such as hypertension, gallbladder disease, stroke, cancers, and atherosclerosis, and also with the onset of obesity in humans and animals. Among the possible beneficial effects of ascorbic acid on obesity-related mechanisms, it has been suggested that this vitamin may: (a) modulate adipocyte lipolysis; (b) regulate the glucocorticoid release from adrenal glands; (c) inhibit glucose metabolism and leptin secretion on isolated adipocytes; (d) lead to an improvement in hyperglycemia and decrease glycosylation in obese-diabetic models; and (e) reduce the inflammatory response. Possibly, all these features could be related with the outstanding antioxidant characteristics of this vitamin. Thus, the present article reviews the up-to-date evidence regarding in vitro and in vivo effects of vitamin C in obesity and its co-morbidities.