punicalagin and Insulin-Resistance

Insulin resistance (IR), as a common pathophysiological basis, is closely related to a variety of metabolic diseases, such as obesity and diabetes. IR is often accompanied by mitochondrial dysfunction which could be induced by a high fat diet. Punicalagin (PU), a natural compound extracted from pomegranate, could ameliorate palmitate-induced IR. However, the underlying mechanisms are not well known. We propose that understanding the proteomic response of mitochondria may help define the mechanisms of PU in the prevention of IR. Most of the mitochondrial proteins are encoded by nuclear genes and transported from cytoplasm. To distinguish newly incorporated proteins responding to stimuli from pre-existing mitochondrial proteome, nascent proteins in HepG2 cells were pulse labeled by an amino acid analog L-azidohomoalanine. Nascent nuclear encoded mitochondrial proteins were enriched by click reaction followed by mass detection. Our data showed that PU increased nuclear encoded protein incorporation to mitochondria in general though the total protein levels remained immobile. To decipher this phenomenon, we tested the protein and mRNA levels of genes related to mitophagy and mitochondrial biogenesis and found that the mitochondrial turnover was accelerated by PU treatment. By the nascent protein labeling strategy and pathway analysis, we enriched the newly incorporated proteins of mitochondria for responding to PU treatment and found that PU induced nascent protein incorporation into mitochondria and enhanced mitochondrial turnover. These findings demonstrate that PU prevents IR by targeting mitochondria, and thus, is an effective natural nutrient beneficial for mitochondrial turnover.

Topics: Hep G2 Cells; Humans; Hydrolyzable Tannins; Insulin Resistance; Mitochondria; Proteomics

Punicalagin (PU)-rich pomegranate peel extract has been shown before to exert protective effects against high fat-induced hepatic damage. The aim of this study is to explore whether and how PU antagonizes hepatic steatosis in Western diet-fed (WD) mice.. The findings suggest that PU improves hepatic steatosis induced by WD, in part through regulating lipid homeostasis and inflammation in liver and adipose tissue and restoring microbiota shift and impaired gut barrier function. Thus, PU can be potentially developed as a potential prevention strategy in combating nonalcoholic fatty liver disease.

Topics: Adiponectin; Animals; Diet, Western; Dysbiosis; Gastrointestinal Microbiome; Hepatitis; Hydrolyzable Tannins; Insulin Resistance; Intra-Abdominal Fat; Lipid Metabolism; Lipid Peroxidation; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Panniculitis

Nowadays, medicinal plants have been widely used everywhere to provide essential care for many disorders including diabetes. Recent reports assumed that the antidiabetic activities of pomegranate aril juice (PAJ) may be ascribed to its punicalagin (PCG). Therefore, the present study evaluated and compared the antidiabetic activities of PAJ and its PCG, and monitored some mechanisms of their actions in streptozotocin-nicotinamide (STZ-NA) type 2 diabetic rats. STZ-NA diabetic rats were given, orally/daily, PAJ (100 or 300 mg/kg body weight, containing 2.6 and 7.8 mg of PCG/kg body weight, respectively), pure PCG (2.6 or 7.8 mg/kg body weight), or distilled water (vehicle) for 6 weeks. PAJ (especially at the high dose) alleviated significantly (P < 0.05-0.001) most signs of type 2 diabetes including body-weight loss, insulin resistance (IR) and hyperglycemia through decreasing serum tumor necrosis factor-α concentration and the expression of hepatic c-Jun N-terminal kinase, and increasing the skeletal muscle weight and the expression of hepatic insulin receptor substrate-1 in STZ-NA diabetic rats. Also, it decreased significantly (P < 0.001) the oxidative liver injury in STZ-NA diabetic rats through decreasing the hepatic lipid peroxidation and nitric oxide production, and improving the hepatic antioxidant defense system. Although the low dose of PCG induced some modulation in STZ-NA diabetic rats, the high dose of PCG did not show any valuable antidiabetic activity, but induced many side effects. In conclusion, PAJ was safer and more effective than pure PCG in alleviating IR and oxidative liver injury in STZ-NA diabetic rats.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Hydrolyzable Tannins; Hyperglycemia; Insulin Receptor Substrate Proteins; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Lipid Peroxidation; Liver; Male; Muscle, Skeletal; Niacinamide; Nitric Oxide; Pomegranate; Rats; Streptozocin; Tumor Necrosis Factor-alpha

Punicalagin (PU) is one of the major ellagitannins found in the pomegranate (Punica granatum), which is a popular fruit with several health benefits. So far, no studies have evaluated the effects of PU on nonalcoholic fatty liver disease (NAFLD). Our work aims at studying the effect of PU-enriched pomegranate extract (PE) on high fat diet (HFD)-induced NAFLD.. PE administration at a dosage of 150 mg/kg/day significantly inhibited HFD-induced hyperlipidemia and hepatic lipid deposition. As major contributors to NAFLD, increased expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukins 1, 4, and 6 as well as augmented oxidative stress in hepatocytes followed by nuclear factor (erythroid-derived-2)-like 2 (Nrf2) activation were normalized through PE supplementation. In addition, PE treatment reduced uncoupling protein 2 (UCP2) expression, restored ATP content, suppressed mitochondrial protein oxidation, and improved mitochondrial complex activity in the liver. In contrast, mitochondrial content was not affected despite increased peroxisomal proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and elevated expression of genes related to mitochondrial beta-oxidation after PE treatment. Finally, PU was identified as the predominant active component of PE with regard to the lowering of triglyceride and cholesterol content in HepG2 cells, and both PU- and PE-protected cells from palmitate induced mitochondrial dysfunction and insulin resistance.. Our work presents the beneficial effects of PE on obesity-associated NAFLD and multiple risk factors. PU was proposed to be the major active component.. By promoting mitochondrial function, eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of NAFLD.

Topics: Animals; Body Weight; Cholesterol; Diet, High-Fat; Disease Models, Animal; Hep G2 Cells; Humans; Hydrolyzable Tannins; Inflammation; Insulin Resistance; Lipid Metabolism; Liver; Lythraceae; Male; Mitochondria; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Plant Extracts; Rats; Sterol Regulatory Element Binding Protein 1; Triglycerides