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Ursolic acid is a naturally occurring pentacyclic triterpenoid in many plants, such as medicinal herbs and food, and was previously found to be an effective phytochemical that protected against high-fat diet-induced hepatic steatosis and liver injury. However, the molecular mechanisms are not fully determined. The present study examined the protective role of ursolic acid against saturated fatty acid-induced lipotoxicity. We found that ursolic acid protected HepG2 (hepatocellular carcinoma, human) cells against palmitate-induced cell death and mitochondrial dysfunction. The protective activity was the result of ursolic acid-induced autophagy, and an autophagy inhibitor prevented this protective effect. Ursolic acid activated/phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and reduced phosphorylation of mammalian target of rapamycin. AMPK gene knockdown by siRNA transfection abolished the protective effect of ursolic acid. Ursolic acid induced autophagy in HepG2 cells to protect against palmitate-induced cell death via an AMPK/mTOR pathway.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA), an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD)-induced obese non-alcoholic fatty liver disease (NAFLD) rat model.Methodology/principal findingsObese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR)-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress.Conclusions/significanceThese results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD.

The detrimental role of hepatic lipotoxicity has been well-implicated in the pathogenesis of NAFLD. Previously, we reported that inhibiting autophagy aggravated saturated fatty acid (SFA)-induced hepatotoxicity. Insulin, a physiological inhibitor of autophagy, is commonly increased within NAFLD mainly caused by insulin resistance. We therefore hypothesized that insulin augments the sensitivity of hepatocyte to SFA-induced lipotoxicity. The present study was conducted via employing human and mouse hepatocytes, which were exposed to SFAs, insulin, or their combination. Unexpectedly, our results indicated that insulin protected hepatocytes against SFA-induced lipotoxicity, based on the LDH, MTT, and nuclear morphological measurements, and the detection from cleaved-Parp-1 and -caspase-3 expressions. We subsequently clarified that insulin led to a rapid and short-period inhibition of autophagy, which was gradually recovered after 1 h incubation in hepatocytes, and such extent of inhibition was insufficient to aggravate SFA-induced lipotoxicity. The mechanistic study revealed that insulin-induced alleviation of ER stress contributed to its hepatoprotective role. Pre-treating hepatocytes with insulin significantly stimulated phosphorylated-Akt and reversed SFA-induced up-regulation of p53. Chemical inhibition of p53 by pifithrin-α robustly prevented palmitate-induced cell death. The PI3K/Akt pathway blockade by its special antagonist abolished the protective role of insulin against SFA-induced lipotoxicity and p53 up-regulation. Furthermore, we observed that insulin promoted intracellular TG deposits in hepatocytes in the present of palmitate. However, blocking TG accumulation via genetically silencing DGAT-2 did not prevent insulin-protected lipotoxicity. Our study demonstrated that insulin strongly protected against SFA-induced lipotoxicity in hepatocytes mechanistically through alleviating ER stress via a PI3K/Akt/p53 involved pathway but independently from autophagy.

Background: There has been increased recognition that prenatal or perinatal nutrition has an effect on the development of type 2 diabetes (T2D) in adulthood, although studies that have directly examined whether the effect could be transmitted to the next generation remain sparse. Objective: We investigated the role of prenatal exposure to the Chinese famine in affecting future T2D risk in adulthood in 2 consecutive generations. Design: A total of 1034 families, including 2068 parents [parental generation (F1)] and 1183 offspring [offspring generation (F2)], were recruited from the Suihua rural area that was affected by the Chinese Famine of 1959-1961. Participants born between 1 October 1959 and 30 September 1961 were defined as famine exposed, and those born between 1 October 1962 and 30 September 1964 were defined as nonexposed. The F2 were classified as having 1) no parent exposed to famine,) only a mother exposed to famine, 3) only a father exposed to famine, or 4) both parents exposed to famine. Classical risk factors for T2D as well as fasting-glucose- and oral-glucosetolerance tests were measured in both the F1 and F2. Results: Prenatal exposure to famine was associated with elevated risks of hyperglycemia (multivariable-adjusted OR: 1.93; 95% CI: 1.51, 2.48) and T2D (OR: 1.75; 95% CI: 1.20, 2.54) in adulthood in F1. Furthermore, compared with the offspring of nonexposed parents, the F2 with exposed parents-- especially both exposed parents--had increased hyperglycemia risk (OR: 2.02; 95% CI: 1.12, 3.66) in adulthood. Conclusion: Prenatal exposure to famine remarkably increases hyperglycemia risk in 2 consecutive generations of Chinese adults independent of known T2D risk factors, which supports the notion that prenatal nutrition plays an important role in the development of T2D across consecutive generations of Chinese adults. [ABSTRACT FROM AUTHOR]