Identification of a natural PLA2 inhibitor from the marine fungus Aspergillus sp. c1 for MAFLD treatment that suppressed lipotoxicity by inhibiting the IRE-1α/XBP-1s axis and JNK signaling

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

Mechanism of action of lipotoxicity in nonalcoholic steatohepatitis / 临床肝胆病杂志

Nonalcoholic steatohepatitis (NASH) is an important part of the exacerbation of nonalcoholic fatty liver disease (NAFLD), and inflammation and liver damage are important pathological features of this stage. As one of the pathogenic mechanisms of NASH, lipotoxicity can regulate liver inflammation and hepatocyte apoptosis through multiple pathways. Therefore, this article elaborates on the specific regulatory mechanism of lipotoxicity on NASH from the two aspects of inflammation and hepatocyte apoptosis, which involves a variety of liver nonparenchymal cells and various signaling pathways such as JNK, NF-κB, and caspase-mediated cell apoptosis, so as to provide new ideas for the diagnosis and treatment of NASH in clinical practice.

Palmitic acid inhibits the synthesis and secretion of thyroglobulin of rat thyroid follicular epithelial cell by downregulating thyrotropin receptor / 中华内分泌代谢杂志

Objective:Exploring the role of thyrotropin receptor(TSHR) in lipotoxicity-induced thyroid function damage.Methods:Rat thyroid follicular epithelial cells(RTC) were stimulated with different doses of palmitic acid(PA), and the lipid content of the cells was observed through Oil Red O staining. The expression levels of TSH receptor(TSHR), Ttf1, and SSBP1 mRNA and protein in each group were detected using RT-PCR and Western blot. The TSHR protein level in the cell culture supernatant was measured using ELISA. Membrane TSHR was assessed through immunofluorescence and compared with the control group. We used PA to stimulate the TSHR over-expression(TSHR OE) and normal RTC, as PA+ TSHR OE group and PA group respectively, then testing Tg mRNA and protein, cAMP and Tg in cell supernatants levels, then comparing with the control.Results:RTC were stained into peau d′orange in PA groups. Compared with the control group, we found TTf1, SSBP1 and TSHR mRNA as well as protein levels in PA groups were decreased(all P<0.05), TSHR of the cell membrane and supernatants were reduced(all P<0.05), characterizing dose-dependent changes partly. Moreover, we found in PA group Tg mRNA level was downregulated( P<0.05), Tg protein levels were reduced in the supernatants and cells( P<0.05), cAMP level was decreased in cells( P<0.05); in TSHR OE group, Tg mRNA level was upregulated( P<0.05), Tg protein levels in cells and supernatants were increased(all P<0.05), cAMP level was similar. Compared with the PA group, we found in PA+ TSHR OE group Tg mRNA level was upregulated( P<0.05), Tg protein levels were increased in the supernatants and cells(all P<0.05), cAMP level was elevated in cells( P<0.05). Conclusion:PA induces lipid deposition in RTC, decreased synthesis and secretion of Tg. This effect is likely achieved through the downregulation of the TSHR/cAMP signaling pathway.

Study on the relationship between onset age and ketosis in newly diagnosed type 2 diabetes patients / 公共卫生与预防医学

Objective To explore the relationship between the age of onset and ketosis in patients with newly diagnosed type 2 diabetes mellitus (T2DM), and to provide reference for clinical early intervention and treatment of ketosis according to the characteristics of age. Methods A single center cross-sectional study was conducted to study newly diagnosed T2DM patients who were hospitalized in the Endocrinology Department of Zhongnan Hospital of Wuhan University from January 2016 to December 2019. According to the age of onset, they were divided into young group, middle-aged group and old group. The general clinical data were analyzed and compared. Spearman correlation analysis and multivariate logistic regression were used to analyze the correlation between age and ketosis. Results The proportion of ketosis, males, overweight/obesity, MS, TyG, BMI, β-HB, and TG levels in the young group were significantly higher than those in the middle-aged and old groups, and HbA1c, HOMA-IR, MBS, and OGTT0h were significantly higher than those in the old group. HDL-C in the young group was significantly lower than that in the middle-aged group and old group, and AUGinsulin and IRT2h were significantly lower than those in the old group (P＜0.05). Spearman correlation analysis showed that age was positively correlated with HDL-C and AUGinsulin, and negatively correlated with BMI, TG, HbA1c, β-HB, HOMA-IR, and TyG (P<0.05). Multivariate logistic regression analysis showed that compared with the old group, the OR values of ketosis in the middle-aged group and the young group were 2.584 and 3.870, respectively (P<0.05). Conclusion Early onset age can increase the risk of ketosis in newly diagnosed T2DM patients, and it is necessary to strengthen early intervention and comprehensive treatment for young patients with disease onset.

Role of lipotoxicity in the development and progression of nonalcoholic fatty liver disease / 临床肝胆病杂志

Nonalcoholic fatty liver disease (NAFLD) is currently the leading cause of abnormal liver biochemical parameters, but the mechanism of its development and progression remains unclear and there is a lack of effective treatment methods. This article reviews that lipotoxicity drives the transformation of NAFLD to nonalcoholic steatohepatitis and liver cirrhosis by triggering the three pathological responses in the liver, i.e., endoplasmic reticulum stress, cell death, and inflammation. It is believed that lipotoxicity is an important factor that promotes the progression of NAFLD to inflammation and fibrosis, which provides a new method for the prevention and treatment of NAFLD.

Dual Roles of Lipid in Oocyte Development / 中国生物化学与分子生物学报

Oocytes are the germ cells of female animals, which determine the reproductive ability of female animals. A large amount of lipids are present in oocytes, which are found in lipid droplets mostly in the form of triglycerides. The size, color and distribution pattern of lipid droplets are associated with the developmental ability of oocytes. Triglycerides could be lipolyzed into fatty acids in oocytes. The fatty acid β-oxidation is an important energy source for the development of oocytes and early embryos. However, excessive lipid deposition would increase levels of reactive oxygen species (ROS), resulting in the dysfunction of mitochondria and endoplasmic reticulum, eventually impairing the subsequent oocyte development. By summarizing the positive and negative effects of lipids on oocyte development, this review shows the dual roles of lipids in oocyte development, and discusses the effects of lipids on oocyte development.

Ferulic acid protects palmitic acid-induced lipotoxicity in hepatocytes via inhibiting p38 MAPK / 中国临床药理学与治疗学

AIM: To investigate the protective effect of ferulic acid on palmitic acid-induced lipotoxicity in HepG2 cells and to explore its potential molecular mechanisms. METHODS: HepG2 cells were induced by palmitic acid to establish a lipotoxicity model, while ferulic acid was added prior to palmitic acid treatment. Lactate dehydrogenase (LDH) was used to detect cell damage. Methyl azozole trace enzyme reaction is used for 3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide (MTT) was employed to detect cell viability. The molecular mechanisms of the protective effect of ferulic acid was analyzed by Western Blotting. RESULTS: There was no cytotoxic effect of different concentrations of ferulic acid (25, 50, 100, 200 μmol/L) treatment on HepG2 cells (P>0.05). Ferulic acid intervention significantly inhibited palmitic acid-induced cell death and improved palmitic acid-induced reduction of cell mitochondrial membrane potential (P<0.05). The activation of p38 significantly enhanced palmitic acid-induced hepatocellular lipotoxicity (P<0.05), while inhibition of p38 significantly improved palmitic acid-induced cell damage (P<0.05). In addition, ferulic acid significantly inhibited the upregulation of p38 phosphorylation by palmitic acid treatment (P<0.05). p38 activator exposure blocked the protective effect of ferulic acid on lipotoxicity (P<0.05). CONCLUSION: Ferulic acid effectively improves hepatocellular injury induced by lipotoxicity.The inhibition of p38 signaling pathway is potentially involved in its protective effect. Ferulic acid may be an effective factor in the prevention and treatment of liver disease with lipotoxicity as a major pathological characteristic.

Salvianolic acid A improves palmitie acid-induced lipotoxicity in cardiomyocyte via inhibiting TLR4/JNK MAPK / 中国临床药理学与治疗学

AIM: To reveal the ameliorative effect of salvianolic acid A on palmitie acid-induced lipotoxicity in H9C2 cells and to explore its potential molecular mechanisms preliminarily. METHODS: H9C2 cell were induced by palmitie acid to establish a lipotoxicity model, while salvianolic acid A was added prior to palmitie acid treatment. Lactate dehydrogenase (LDH) was employed to detect cell damage. Cell counting Kit-8 was used to detect cell viability. The changes of mitochondrial membrane potential in cardiomyocyte were observed by rhodamine 123 staining. The molecular mechanisms of the ameliorative effect of salvianolic acid A was analyzed by Western Blotting. RESULTS: Palmitie acid at a concentration of 400 μmol/L significantly caused lipotoxicity damage to H9C2 cells (P0.05). Salvianolic acid A intervention significantly improved lipotoxicity-induced cell death and reduction of cell mitochondrial membrane potential (P<0.05). The activation of toll-like receptor 4 (TLR4) significantly enhanced lipotoxicity-induced cell damage (P<0.05), while inhibition of TLR4 significantly reduced palmitie acid-induced lipotoxicity (P<0.05). In addition, salvianolic acid A effectively inhibited the upregulation of TLR4 and the downstream c-Jun N-terminal kinase (JNK MAPK) of TLR4 by palmitie acid treatment (P<0.05). CONCLUSION: Salvianolic acid A effectively improves lipotoxicity-induced cardiomyocyte damage. The inhibition of p38 signaling pathway is potentially involved in its protective effect. The protective effect may be related to the inhibition of TLR4/JNK MAPK signaling pathway, providing a potential molecular target for the prevention and treatment of lipotoxic cardiomyopathy.

Salvianolic acid A activates AMPK and SIRT1 to reduce palmitic acid-induced lipotoxicity in hepatocyte / 中国临床药理学与治疗学

AIM: To investigate the protective affect of salvianolic acid A on palmitic acid-induced lipotoxicity in hepatocyte and its potential molecular mechanism. METHODS: The lipotoxicity model of AML12 hepatocytes induced by PA was established. Different concentrations of Sal A (20, 40, 80, 120 μmol/L) were intervened. The hepatocyte injury was detected by the Lactate dehydrogenase (LDH) method, the intracellular triglyceride (TG) content was detected by enzyme assay and the lipid droplets were observed by Bodipy staining, cell viability was detected by MTT, Intracellular reactive oxygen species (ROS) were detected by 2'eci'- dichlorofluorescein diacetate (DCFH-DA) and fluorescence microscope. Mitochondrial membrane potential was detected by rhodamine 123 and fluorescence microscope. The expression of phosphorylation of AMP-activated protein kinase (AMPK) protein and silent information regulator 1 (SIRT1) protein were observed by Western blot. RESULTS: Model of hepatocyte lipotoxicity was established after intervented for 12 h in vitro with PA (0.5 mmol/L). Different concentrations of Sal A could significantly reduce the lipid deposition and hepatocytes injury induced by PA (P<0.05), and the protective effect was dose-dependent. Secondly, Sal A could significantly improve cell mitochondrial membrane potential (P<0.01) and abate the ROS level of hepatocytes induced by PA (P<0.01). In addition, PA could significantly inhibit AMPK and SIRT1 protein expression (P<0.05). Salvianolic acid A can significantly up-regulate SIRT1 and AMPK protein expression (P<0.05). CONCLUSION: Sal A improves PA induced lipotoxicity in hepatocyte, AMPK and SIRT1 may be a potential molecular target.

Sangguayin preparation prevents palmitate-induced apoptosis by suppressing endoplasmic reticulum stress and autophagy in db/db mice and MIN6 pancreatic β-cells / 中国天然药物

Sangguayin preparation (SGY-P) is refined from the traditional Chinese medicinal compound Sangguayin, which "clears heat and promotes fluid" and "tonifies kidney and spleen" for "Xiaoke", commonly known as 'Diabetes mellitus' in clinics. Previous studies have shown that SGY-P could reduce insulin resistance and repair damaged pancreas in db/db mice, but the underlying mechanisms were unclear. Here, we investigated whether treatment with SGY-P could protect pancreatic β-cells from apoptosis and uncovered the underlying mechanisms. db/db mice were used to observe the hypoglycemic and islet protective effect in vivo. Apoptosis was induced in mouse insulinoma 6 (MIN6) cells by palmitate, following which the cells were treated with SGY-P for elucidating the anti-apoptotic mechanism in vitro. Cell viability and nuclear morphology were detected by CCK-8 assay and Hoechst 33258 staining. The expression levels of apoptosis-, endoplasmic reticulum (ER) stress-, and autophagy-related proteins were measured by western blot. The results showed that SGY-P reduced fasting blood glucose, pancreatic pathological changes, and islet β-cell apoptosis in db/db mice. Palmitate-induced apoptosis in MIN6 cells was decreased by SGY-P treatment. Hence, SGY-P therapy exhibited a protective effect on pancreatic β-cells by decreasing the expression of cleaved caspase-3, cleaved PARP and Bax, and increasing Bcl-2 by suppressing ER stress (Bip/XBP1/IRE1α/CHOP/Caspase-12) and autophagy (LC3/p62/Atg5) pathways.2/Atg5) pathways.

Nutrigenomics as a tool in the prevention of lipotoxicity: the case of soy protein

Abstract Obesity is associated with an increase of several metabolic disorders leading to the development of diseases such as type 2 diabetes and cardiovascular disease. This is due in part to the ectopic accumulation of triglycerides in organs that are non-adipose tissues, leading to lipotoxicity. Particularly, in the liver, the accumulation of lipids, mainly of triglycerides, leads to the formation of fatty liver. The accumulation of lipids in skeletal muscle and pancreas associates with insulin resistance and a decrease in insulin secretion, respectively. In addition, it has been suggested that dysbiosis of the gut microbiota can contribute to the process of lipid accumulation in non-adipose tissues, especially in the liver. The aim of the present review is to highlight the mechanisms associated with the development of lipotoxicity, and how with the advances in nutrigenomics, it is now possible to understand the molecular mechanisms by which some nutrients can attenuate the ectopic accumulation of triglycerides in non-adipose tissues. Particularly, we emphasize research conducted on the molecular mechanisms of action of soy protein and some of its isoflavones, and how these can reduce lipotoxicity by preventing the accumulation of lipids in the liver, skeletal muscle, and pancreas, as well as their role on the gut microbiota to attenuate the development of fatty liver. Thus, nutrigenomics is opening new dietary strategies based on several functional foods that can be used to ameliorate the pathologies associated with lipotoxicity.

Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic ß-cells

BACKGROUND: Free fatty acid receptor 1 (FFAR1) is G-protein coupled receptor predominantly expressed in pancreatic ß-cells that is activated by a variety of free fatty acids (FFAs). Once activated, it promotes glucose-stimulated insulin secretion (GSIS). However, increased levels of FFAs lead to lipotoxicity, inducing loss of ß-cell function. FFAR1 plays a key role in the development of type 2 diabetes (T2D), and previous studies have indicated the importance of developing anti-diabetic therapies against FFAR1, although its role in the regulation of ß-cell function remains unclear. The present study investigated the role of FFAR1 under lipotoxic conditions using palmitic acid (PA). The rat insulinoma 1 clone 832/13 (INS-1 832/13) cell line was used as a model as it physiologically resembles native pancreatic ß-cells. Key players of the insulin signaling pathway, such as mTOR, Akt, IRS-1, and the insulin receptor (INSR1ß), were selected as candidates to be analyzed under lipotoxic conditions. RESULTS: We revealed that PA-induced lipotoxicity affected GSIS in INS-1 cells and negatively modulated the activity of both IRS-1 and Akt. Reduced phosphorylation of both IRS-1 S636/639 and Akt S473 was observed, in addition to decreased expression of both INSR1ß and FFAR1. Moreover, transient knockdown of FFAR1 led to a reduction in IRS-1 mRNA expression and an increase in INSR1ß; mRNA. Finally, PA affected localization of FFAR1 from the cytoplasm to the perinucleus. CONCLUSIONS: In conclusion, our study suggests a novel regulatory involvement of FFAR1 in crosstalk with mTOR-Akt and IRS-1 signaling in ß-cells under lipotoxic conditions.

Effects of Cigu Xiaozhi Pills on Lipotoxicity and Oxidative Stress in Rats with Non-alcoholic Steatohepatitis / 中国中医药信息杂志

Objective To explore the effects of Cigu Xiaozhi Pills on lipotoxicity and oxidative stress in rats with non-alcoholic steatohepatitis (NASH); To discuss relevant mechanism of action. Methods SD rats were divided into six groups randomly:normal control group,model group,positive medicine group,Cigu Xiaozhi Pills high-,medium-, and low-dose groups. NASH model was established by feeding rats with high fat diet for 12 weeks. At the same time, the model rats were given medicine intervention. At the end of 12 weeks, all the experimental animals were killed and the liver and serum were taken. Serum samples were taken for detection of ALT, AST, TG, TC, T-SOD, LDL-C, MDA, GSH-Px and FFA. Liver tissues were taken for detection of T-SOD, MDA, GSH-Px and FFA. The liver histopathological changes were observed under microscope with HE staining. The ultrastructure of liver cells was observed by transmission electron microscope. The fatty degeneration of liver cells was observed by oil red O staining. Results Liver histopathological examination showed that the liver tissue of model group showed moderate to severe steatosis and inflammatory cell infiltration. Compared with normal control group, rat liver wet weight, liver index, ALT, AST, TG, TC, LDL-C, MDA and FFA in serum, and FFA and MDA in liver homogenate in model group significantly increased (P<0.05, P<0.01), while T-SOD and GSH-Px activity in serum and liver homogenate significantly decreased (P<0.05, P<0.01). Compared with model group, Cigu Xiaozhi Pills high-dose group could significantly decrease the elevation of serum ALT, AST, TG, TC, LDL-C, MDA and FFA (P<0.05, P<0.01), but increase T-SOD and GSH-Px activity in serum and liver tissue (P<0.01). The pathological section showed that:compared with model group, the hepatic lobule vacuolar degeneration and fatty degeneration were significantly reduced in Cigu Xiaozhi Pills high-, medium- and low-dose groups, and the inflammatory cell infiltration was improved. Conclusion Cigu Xiaozhi Pills can obviously improve liver function and blood lipid of NASH rat model induced by high-fat diet, enhance antioxidant capacity, reduce lipid peroxidation and achieve the purpose of prevention and treatment of NASH.

The relationship between muscle mitochondrial nutritional overloading and insulin resistance / 영남의대학술지

The incidence of type 2 diabetes mellitus and insulin resistance is growing rapidly. Multiple organs including the liver, skeletal muscle and adipose tissue control insulin sensitivity coordinately, but the mechanism of skeletal muscle insulin resistance has not yet been fully elucidated. However, there is a growing body of evidence that lipotoxicity induced by mitochondrial dysfunction in skeletal muscle is an important mediator of insulin resistance. However, some recent findings suggest that skeletal mitochondrial dysfunction generated by genetic manipulation is not always correlated with insulin resistance in animal models. A high fat diet can provoke insulin resistance despite a coordinate increase in skeletal muscle mitochondria, which implies that mitochondrial dysfunction is not mandatory in insulin resistance. Furthermore, incomplete fatty acid oxidation by excessive nutrition supply compared to mitochondrial demand can induce insulin resistance without preceding impairment of mitochondrial function. Taken together we suggested that skeletal muscle mitochondrial overloading, not mitochondrial dysfunction, plays a pivotal role in insulin resistance.

In Vitro Effect of Fatty Acids Identified in the Plasma of Obese Adolescents on the Function of Pancreatic β-Cells

BACKGROUND: The increase in circulating free fatty acid (FFA) levels is a major factor that induces malfunction in pancreatic β-cells. We evaluated the effect of FFAs reconstituted according to the profile of circulating fatty acids found in obese adolescents on the viability and function of the murine insulinoma cell line (mouse insulinoma [MIN6]). METHODS: From fatty acids obtained commercially, plasma-FFA profiles of three different youth populations were reconstituted: obese with metabolic syndrome; obese without metabolic syndrome; and normal weight without metabolic syndrome. MIN6 cells were treated for 24 or 48 hours with the three FFA profiles, and glucose-stimulated insulin secretion, cell viability, mitochondrial function and antioxidant activity were evaluated. RESULTS: The high FFA content and high polyunsaturated ω6/ω3 ratio, present in plasma of obese adolescents with metabolic syndrome had a toxic effect on MIN6 cell viability and function, increasing oxidative stress and decreasing glucose-dependent insulin secretion. CONCLUSION: These results could help to guide nutritional management of obese young individuals, encouraging the increase of ω-3-rich food consumption in order to reduce the likelihood of deterioration of β-cells and the possible development of type 2 diabetes mellitus.

The relationship between muscle mitochondrial nutritional overloading and insulin resistance / 영남의대학술지

The incidence of type 2 diabetes mellitus and insulin resistance is growing rapidly. Multiple organs including the liver, skeletal muscle and adipose tissue control insulin sensitivity coordinately, but the mechanism of skeletal muscle insulin resistance has not yet been fully elucidated. However, there is a growing body of evidence that lipotoxicity induced by mitochondrial dysfunction in skeletal muscle is an important mediator of insulin resistance. However, some recent findings suggest that skeletal mitochondrial dysfunction generated by genetic manipulation is not always correlated with insulin resistance in animal models. A high fat diet can provoke insulin resistance despite a coordinate increase in skeletal muscle mitochondria, which implies that mitochondrial dysfunction is not mandatory in insulin resistance. Furthermore, incomplete fatty acid oxidation by excessive nutrition supply compared to mitochondrial demand can induce insulin resistance without preceding impairment of mitochondrial function. Taken together we suggested that skeletal muscle mitochondrial overloading, not mitochondrial dysfunction, plays a pivotal role in insulin resistance.

Beneficios de los ácidos grasos poliinsaturados de cadena larga n-3 en la enfermedad por hígado graso no alcohólico / Benefits of n-3 long-chain polyunsaturated fatty acids in non-alcoholic fatty liver disease

La enfermedad por hígado graso no alcohólico (EHGNA) se asocia comúnmente con las características clínicas del síndrome metabólico como la obesidad, resistencia a la insulina y dislipidemia. La importancia clínica se debe a su elevada prevalencia (30% de la población general) y su amplio espectro de daño histológico que va desde la esteatosis simple generalmente no progresiva, a la esteatohepatitis no alcohólica, que puede conducir a cirrosis, carcinoma hepatocelular, e insuficiencia hepática. En la actualidad, se han caracterizado diferentes factores que conllevan a esta enfermedad hepática, destacándose principalmente el alto contenido de ácidos grasos libres y la resistencia a insulina. El exceso de ácidos grasos libres puede desencadenar lipotoxicidad hepática originada por un alto consumo de ácidos grasos saturados, ácidos grasos trans y carbohidratos, así como por un aumento de los radicales libres y del estrés del retículo endoplásmico. En lo que concierne a los ácidos grasos poliinsaturados de cadena larga n-3 (AGPICL n-3), se han atribuido múltiples beneficios para la salud humana. Los AGPICL n-3 EPA y DHA tienen efectos protectores en la salud cardiovascular y en la funcionalidad e integridad del sistema nervioso central. Actualmente el uso nutricional de ambos ácidos grasos es cada vez más amplio, atribuyendo sus efectos positivos no solamente al tratamiento de las enfermedades cardiovasculares y neurodegenerativas, sino también considerándolos una alternativa eficaz en el manejo de nutricional de la EHGNA. El presente trabajo analiza el uso potencial de los AGPICL n-3 en la prevención y manejo nutricional de la EHGNA.

Nonalcoholic fatty liver disease (NAFLD) is commonly associated with the clinical features of the metabolic syndrome including obesity, insulin resistance and dyslipidemia. NAFLD. Is of clinical relevance because its high prevalence (30% of the general population) and broad spectrum of histological damage, ranging from simple steatosis that is generally non progressive, to nonalcoholic steatohepatitis which can lead to cirrhosis, hepatoce-llular carcinoma, and liver failure. At present, different factors have been identified that lead to this liver disease, highlighting the high content of free fatty acids and insulin resistance. In this regard, excess of free fatty acids caused by a high intake of sa-turated fatty acids, trans fatty acids and of carbohydrates as well the increased formation free radicals that stress the endoplasmic reticulum, can trigger liver lipotoxicity. Regarding fatty acids, n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) have been associated to many benefits for human health. n-3 LCPUFA, such as EPA and DHA, have protective roles in cardiovascular health and in the functionality and integrity of the central nervous system. Currently, the possible therapeutic uses of these fatty acids is expanding, attributing their positive effects not only for the treatment of cardiovascular and neurodegenerative diseases, but also seeing it as an effective alternative in the management of NAFLD. The present review analyzes the potential use of n-3 LCPUFA in the treatment and protection of NAFLD.

Novel Molecular Mechanisms in the Development of Non-Alcoholic Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in adults and children worldwide. NAFLD has become a severe health issue and it can progress towards a more severe form of the disease, the non-alcoholic steatohepatitis (NASH). A combination of environmental factors, host genetics, and gut microbiota leads to excessive accumulation of lipids in the liver (steatosis), which may result in lipotoxicity and trigger hepatocyte cell death, liver inflammation, fibrosis, and pathological angiogenesis. NASH can further progress towards liver cirrhosis and cancer. Over the last few years, cell-derived extracellular vesicles (EVs) have been identified as effective cell-to-cell messengers that transfer several bioactive molecules in target cells, modulating the pathogenesis and progression of NASH. In this review, we focused on recently highlighted aspects of molecular pathogenesis of NASH, mediated by EVs via their bioactive components. The studies included in this review summarize the state of art regarding the role of EVs during the progression of NASH and bring novel insight about the potential use of EVs for diagnosis and therapeutic strategies for patients with this disease.

An insight into diabesity – A short review.

Diabetes and obesity are both increasing dramatically in the United States of America and other parts of the world. One third of the American population (34%) are obese (BMI >30 kg/m2). Eleven percent of the population over 20 years of age have type 2 diabetes. Significant increases are predicted by 2050, which is significant because both diabetes and obesity are independent risk factors for hosts of other diseases, as well as risk factors for each other. These conditions constitute major sources of morbidity and mortality, as well as financial loss through impairment of abilities to work, and by creating and exaggerating disease leading to increased expense of healthcare, and increased need in frequency of healthcare. T-Bet Transcription Factor is one mechanism linking both diabetes and obesity interaction. Particular T-Bet genotypes result in varied body-type (mass/obesity) to insulin sensitivity profiles. Lipotoxicity is another linking factor between obesity and type 2 diabetes mellitus. Visceral adiposity accelerates development of insulin resistance by causing chronic increase in fatty acids in circulation, causing reduction in usage of glucose as a cellular energy source. Central obesity is particularly disposing to this kind of insulin resistance development. Cytokine, adipokines including tumor necrosis factor, IL-6, resisitin, retinol binding protein 4 and others are linked in development of insulin resistance as well. Mitochondrial dysfunction has also been identified as a factor in the correlation between these 2 diseases. Causal genes such as PPARG, KCNJ11, melanocortin-4 gene, TCF7L2 variants and others are also implicated and are actively being investigated further to elucidate complexities of these mechanisms and allow for therapeutic interventional opportunities in the future.

Lipoic Acid Prevents the Changes of Intracellular Lipid Partitioning by Free Fatty Acid

BACKGROUND/AIMS: It is suggested that the hepatic lipid composition is more important than lipid quantity in the pathogenesis of non-alcoholic steatohepatitis. We examined whether lipoic acid (LA) could alter intrahepatic lipid composition and free cholesterol distribution. METHODS: HepG2 cells were cultured with palmitic acid (PA) with and without LA. Apoptosis, changes of the mitochondrial structure, intracellular lipid partitioning, and reactive oxygen species (ROS) activity were measured. RESULTS: Free fatty acid (FA) increased apoptosis, and LA co-treatment prevented this lipotoxicity (apoptosis in controls vs PA vs PA+LA, 0.5% vs 19.5% vs 1.6%, p<0.05). LA also restored the intracellular mitochondrial DNA copy number (553+/-33.8 copies vs 291+/-14.55 copies vs 421+/-21.05 copies, p<0.05) and reversed the morphological changes induced by PA. In addition, ROS was increased in response to PA and was decreased in response to LA co-treatment (41,382 relative fluorescence unit [RFU] vs 43,646 RFU vs 41,935 RFU, p<0.05). LA co-treatment increased the monounsaturated and polyunsaturated FA concentrations and decreased the total saturated FA fraction. It also prevented the movement of intracellular free cholesterol from the cell membrane to the cytoplasm. CONCLUSIONS: LA opposes free FA-generated lipotoxicity by altering the intracellular lipid composition and free cholesterol distribution.