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1.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199317

RESUMO

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Antígenos CD/metabolismo , Compostos Benzidrílicos/farmacologia , Biópsia , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Glucose/metabolismo , Glucosídeos/farmacologia , Homeostase/efeitos dos fármacos , Resistência à Insulina , Lactosilceramidas/metabolismo , Lipidômica , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo
2.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205850

RESUMO

Left untreated, nonalcoholic fatty liver disease can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and end-stage liver disease. To date, few if any therapies have proven effective against NASH with fibrosis. Quantification and qualification of hepatic scar might enable development of more effective targeted therapies. In a murine model of NASH induced by diet, we characterized fibrillar collagen deposition within the hepatic parenchyma. At harvest, livers from the modified diet cohort exhibited NASH with fibrosis. Transcriptomic analysis of hepatic tissue revealed increased col1a1, col1a2, and col3a1, each of which correlated directly with hepatic hydroxyproline content. Circular polarized microscopic analysis of Picrosirius red-stained liver sections revealed deposition of collagen type I within the parenchyma. Development of therapeutics designed to mitigate collagen type I accumulation might prove effective in NASH with fibrosis.


Assuntos
Colágeno Tipo III/genética , Colágeno Tipo I/genética , Colágeno/metabolismo , Fast Foods/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Estudos de Casos e Controles , Colágeno/genética , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Microscopia de Polarização , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Regulação para Cima
3.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208774

RESUMO

Bile acids (BA) play a significant role in the pathophysiology of nonalcoholic steatohepatitis (NASH). The present study evaluates the modulation of bile acid metabolomics by atorvastatin, a cholesterol-lowering agent commonly used to treat cardiovascular complications accompanying NASH. NASH was induced in mice by 24 weeks of consuming a high-saturated fat, high-fructose, and high-cholesterol diet (F), with atorvastatin administered orally (20 mg/kg/day) during the last three weeks. Biochemical and histological analyses confirmed the effectiveness of the F diet in inducing NASH. Untreated NASH animals had significantly reduced biliary secretion of BA and increased fecal excretion of BA via decreased apical sodium-dependent bile salt transporter (Asbt)-mediated reabsorption. Atorvastatin decreased liver steatosis and inflammation in NASH animals consistently with a reduction in crucial lipogenic enzyme stearoyl-coenzyme A (CoA) desaturase-1 and nuclear factor kappa light chain enhancer of activated B-cell pro-inflammatory signaling, respectively. In this group, atorvastatin also uniformly enhanced plasma concentration, biliary secretion and fecal excretion of the secondary BA, deoxycholic acid (DCA). However, in the chow diet-fed animals, atorvastatin decreased plasma concentrations of BA, and reduced BA biliary secretions. These changes stemmed primarily from the increased fecal excretion of BA resulting from the reduced Asbt-mediated BA reabsorption in the ileum and suppression of synthesis in the liver. In conclusion, our results reveal that atorvastatin significantly modulates BA metabolomics by altering their intestinal processing and liver synthesis in control and NASH mice.


Assuntos
Atorvastatina/farmacologia , Ácidos e Sais Biliares/metabolismo , Homeostase , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Biomarcadores , Dieta Hiperlipídica , Modelos Animais de Doenças , Fígado/metabolismo , Camundongos , Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/biossíntese
4.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204274

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide, affecting both adults and children and will result, in the near future, as the leading cause of end-stage liver disease. Indeed, its prevalence is rapidly increasing, and NAFLD is becoming a major public health concern. For this reason, great efforts are needed to identify its pathogenetic factors and new therapeutic approaches. In the past decade, enormous advances understanding the gut-liver axis-the complex network of cross-talking between the gut, microbiome and liver through the portal circulation-have elucidated its role as one of the main actors in the pathogenesis of NAFLD. Indeed, evidence shows that gut microbiota is involved in the development and progression of liver steatosis, inflammation and fibrosis seen in the context of NAFLD, as well as in the process of hepatocarcinogenesis. As a result, gut microbiota is currently emerging as a non-invasive biomarker for the diagnosis of disease and for the assessment of its severity. Additionally, to its enormous diagnostic potential, gut microbiota is currently studied as a therapeutic target in NAFLD: several different approaches targeting the gut homeostasis such as antibiotics, prebiotics, probiotics, symbiotics, adsorbents, bariatric surgery and fecal microbiota transplantation are emerging as promising therapeutic options.


Assuntos
Suscetibilidade a Doenças , Trato Gastrointestinal/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais , Ácidos e Sais Biliares/metabolismo , Biomarcadores , Gerenciamento Clínico , Metabolismo Energético , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Humanos , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/terapia , Permeabilidade , Medicina de Precisão/métodos
5.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072586

RESUMO

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been rapidly increasing worldwide. A choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) has been used to create a mouse model of nonalcoholic steatohepatitis (NASH). There are some reports on the effects on mice of being fed a CDAHFD for long periods of 1 to 3 months. However, the effect of this diet over a short period is unknown. Therefore, we examined the effect of 1-week CDAHFD feeding on the mouse liver. Feeding a CDAHFD diet for only 1-week induced lipid droplet deposition in the liver with increasing activity of liver-derived enzymes in the plasma. On the other hand, it did not induce fibrosis or cirrhosis. Additionally, it was demonstrated that CDAHFD significantly impaired mitochondrial respiration with severe oxidative stress to the liver, which is associated with a decreasing mitochondrial DNA copy number and complex proteins. In the gene expression analysis of the liver, inflammatory and oxidative stress markers were significantly increased by CDAHFD. These results demonstrated that 1 week of feeding CDAHFD to mice induces steatohepatitis with mitochondrial dysfunction and severe oxidative stress, without fibrosis, which can partially mimic the early stage of NASH in humans.


Assuntos
Deficiência de Colina/complicações , Dieta Hiperlipídica/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Gluconeogênese , Mediadores da Inflamação/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos , Lipogênese , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Fenótipo
6.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065331

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and represents the hepatic expression of several metabolic abnormalities of high epidemiologic relevance. Fat accumulation in the hepatocytes results in cellular fragility and risk of progression toward necroinflammation, i.e., nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Several pathways contribute to fat accumulation and damage in the liver and can also involve the mitochondria, whose functional integrity is essential to maintain liver bioenergetics. In NAFLD/NASH, both structural and functional mitochondrial abnormalities occur and can involve mitochondrial electron transport chain, decreased mitochondrial ß-oxidation of free fatty acids, excessive generation of reactive oxygen species, and lipid peroxidation. NASH is a major target of therapy, but there is no established single or combined treatment so far. Notably, translational and clinical studies point to mitochondria as future therapeutic targets in NAFLD since the prevention of mitochondrial damage could improve liver bioenergetics.


Assuntos
Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Humanos , Peroxidação de Lipídeos/fisiologia , Oxirredução , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo
7.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062716

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required.


Assuntos
Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Compostos Benzidrílicos/toxicidade , Cumestrol/toxicidade , Dioxinas/toxicidade , Disruptores Endócrinos/classificação , Genisteína/toxicidade , Humanos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/patologia , Fenóis/toxicidade , Fitoestrógenos/toxicidade , Bifenilos Policlorados/toxicidade
8.
Int J Mol Sci ; 22(9)2021 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-34065108

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is strongly linked to the global epidemic of obesity and type 2 diabetes mellitus (T2DM). Notably, NAFLD can progress from the mildest form of simple steatosis to nonalcoholic steatohepatitis (NASH) that increases the risk for hepatocellular carcinoma (HCC), which is a malignancy with a dismal prognosis and rising incidence in the United States and other developed counties, possibly due to the epidemic of NAFLD. Metformin, the first-line drug for T2DM, has been suggested to reduce risks for several types of cancers including HCC and protect against NASH-related HCC, as revealed by epidemical studies on humans and preclinical studies on animal models. This review focuses on the pathogenesis of NASH-related HCC and the mechanisms by which metformin inhibits the initiation and progression of NASH-related HCC. Since the functional role of immune cells in liver homeostasis and pathogenesis is increasingly appreciated in developing anti-cancer therapies on liver malignancies, we discuss both the traditional targets of metformin in hepatocytes and the recently defined effects of metformin on immune cells.


Assuntos
Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metformina/farmacologia , Animais , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/prevenção & controle , Dano ao DNA , Progressão da Doença , Suscetibilidade a Doenças , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/prevenção & controle , Macrófagos/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Fatores de Risco
9.
Zhonghua Gan Zang Bing Za Zhi ; 29(5): 462-467, 2021 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-34107585

RESUMO

Objective: To investigate the effect of baicalein in improving non-alcoholic fatty liver disease caused by high fat-induced oxidative damage in mice. Methods: Male C57BL/6J mice weighing 18-20 g were randomly divided into 4 groups: normal control group (C, 10% fat for energy), high-fat group (H, 60% fat for energy), high-fat + scutellaria baicalein group (H+B, baicalein: 400 mg·kg(-1)·bw(-1)), and baicalein control group (B, baicalein: 400 mg·kg(-1)·bw(-1)). After 12 weeks, mice were sacrificed, and the tissue samples were collected. Liver pathological changes were observed by hematoxylin and eosin staining. Mitochondrial morphology was examined by ultramicropathology. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and mitochondrial membrane potential (MMP) changing levels in the liver were determined by kit. Sestrin2 and protein carbonylation (PCOS) levels were detected by Western blotting. Small interfering RNA (siRNA) was used to knock-down the Sestrin2 protein expression in HepG2 cells. Intramyocellular lipid changes in HepG2 cells was detected by fluorescent dye BODIPY493/503. One way ANOVA was used LSD pairwise comparison method was used to test the statistical difference. Results: Compared with the normal control group, high-fat fed caused significant fatty degeneration, decreased GSH and SOD levels (P ​​< 0.05), increased MDA and protein carbonylation levels, and increased Sestrin2 expression (P < 0.05) in mice. Mitochondrial shape changes, swelling, lack of cristae, and MMP was down-regulated by 33.3% (t = 13.456, P ​​< 0.001). Baicalein intervention had effectively inhibited hepatic steatosis and oxidative damage caused by high-fat fed, and further up-regulated Sestrin2 expression, MMP (t = 10.104, P ​​< 0.001), and significantly alleviated liver damage in mice. Sestrin2 expression knock-down had further increased the intracellular lipid deposition and PCOs expression (P ​​< 0.05), and reduced baicalein ability to antagonize lipid deposition and antioxidant capacity in Hep2 cells. Conclusion: Baicalein alleviate non-alcoholic fatty liver by regulating Sestrin2 expression and high-fat fed-induced liver oxidative damage.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica/efeitos adversos , Flavanonas , Hepatócitos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo
10.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073834

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease associated with obesity and insulin resistance. Activation of the purinergic receptor P2Y2R has been reported to promote adipogenesis, inflammation and dyslipidemia in adipose tissues in obese mice. However, the role of P2Y2R and its mechanisms in NAFLD remain unknown. We hypothesized that P2Y2R deficiency may play a protective role in NAFLD by modulating lipid metabolism in the liver. In this study, we fed wild type and P2Y2R knockout mice with a high-fat diet (HFD) for 12 weeks and analyzed metabolic phenotypes. First, P2Y2R deficiency effectively improved insulin resistance with a reduction in body weight and plasma insulin. Second, P2Y2R deficiency attenuated hepatic lipid accumulation and injury with reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Third, P2Y2R deficiency decreased the expression of fatty acid synthesis mediators (cluster of differentiation (CD36), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1)); and increased the expression of adipose triglyceride lipase (ATGL), a lipolytic enzyme. Mechanistically, P2Y2R deficiency increased the AMP-activated protein kinase (AMPK) activity to improve mitochondrial fatty acid ß-oxidation (FAO) by regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1A (CPT1A)-mediated FAO pathway. In addition, P2Y2R deficiency increased peroxisome proliferator-activated gamma co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis. Conclusively, P2Y2R deficiency ameliorated HFD-induced hepatic steatosis by enhancing FAO through AMPK signaling and PGC-1α pathway, suggesting P2Y2R as a promising therapeutic target for NAFLD.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Graxos/metabolismo , Lipogênese/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Acetil-CoA Carboxilase/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Peso Corporal , Antígenos CD36/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Dieta Hiperlipídica , Ácido Graxo Sintases/metabolismo , Insulina/sangue , Resistência à Insulina/fisiologia , Lipase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/enzimologia , Obesidade/metabolismo , Receptores Purinérgicos P2Y2/deficiência , Receptores Purinérgicos P2Y2/genética , Estearoil-CoA Dessaturase/metabolismo
11.
Nat Commun ; 12(1): 3320, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083525

RESUMO

Exposure of mice or humans to cold promotes significant changes in brown adipose tissue (BAT) with respect to histology, lipid content, gene expression, and mitochondrial mass and function. Herein we report that the lipid droplet coat protein Perilipin 5 (PLIN5) increases markedly in BAT during exposure of mice to cold. To understand the functional significance of cold-induced PLIN5, we created and characterized gain- and loss-of-function mouse models. Enforcing PLIN5 expression in mouse BAT mimics the effects of cold with respect to mitochondrial cristae packing and uncoupled substrate-driven respiration. PLIN5 is necessary for the maintenance of mitochondrial cristae structure and respiratory function during cold stress. We further show that promoting PLIN5 function in BAT is associated with healthy remodeling of subcutaneous white adipose tissue and improvements in systemic glucose tolerance and diet-induced hepatic steatosis. These observations will inform future strategies that seek to exploit thermogenic adipose tissue as a therapeutic target for type 2 diabetes, obesity, and nonalcoholic fatty liver disease.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Mitocôndrias/metabolismo , Perilipina-5/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Temperatura Baixa/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Dioxóis/farmacologia , Glucose/metabolismo , Humanos , Resistência à Insulina , Lipase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/ultraestrutura , Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Perilipina-5/deficiência , Perilipina-5/genética , Sirtuína 1/metabolismo , Termogênese/genética , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Regulação para Cima
12.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067931

RESUMO

Consumption of high-calorie foods, such as diets rich in fats, is an important factor leading to the development of steatohepatitis. Several studies have suggested how lipid accumulation creates a lipotoxic microenvironment for cells, leading cells to deregulate their transcriptional and translational activity. This deregulation induces the development of liver diseases such as non-alcoholic fatty liver disease (NAFLD) and subsequently also the appearance of hepatocellular carcinoma (HCC) which is one of the deadliest types of cancers worldwide. Understanding its pathology and studying new biomarkers with better specificity in predicting disease prognosis can help in the personalized treatment of the disease. In this setting, understanding the link between NAFLD and HCC progression, the differentiation of each stage in between as well as the mechanisms underlying this process, are vital for development of new treatments and in exploring new therapeutic targets. Perilipins are a family of five closely related proteins expressed on the surface of lipid droplets (LD) in several tissues acting in several pathways involved in lipid metabolism. Recent studies have shown that Plin5 depletion acts protectively in the pathogenesis of liver injury underpinning the importance of pathways associated with PLIN5. PLIN5 expression is involved in pro-inflammatory cytokine regulation and mitochondrial damage, as well as endoplasmic reticulum (ER) stress, making it critical target of the NAFLD-HCC studies. The aim of this review is to dissect the recent findings and functions of PLIN5 in lipid metabolism, metabolic disorders, and NAFLD as well as the progression of NAFLD to HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Perilipina-5/metabolismo , Biomarcadores/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Doenças Metabólicas/metabolismo , Perilipina-5/fisiologia , Microambiente Tumoral/fisiologia
13.
Eur J Clin Invest ; 51(7): e13597, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34032283

RESUMO

BACKGROUND: Social containment measures imposed in Europe during the lockdown to face COVID-19 pandemic can generate long-term potential threats for metabolic health. METHODS: A cohort of 494 non-COVID-19 subjects living in 21 EU countries were interviewed by an anonymous questionnaire exploring anthropometric and lifestyle changes during 1-month lockdown. A subgroup of 41 overweight/obese Italian subjects with previously diagnosed nonalcoholic fatty liver (NAFLD) joined the study following a 12-month follow-up period promoting weight loss by healthy lifestyle. RESULTS: During the lockdown, body weight increased in 55% of subjects (average 2.4 ± 0.9 kg). Weight change increased with age, but not baseline body mass index. Subjects living in Italy had greater weight gain than those living in other European Countries. Weight gain during the lockdown was highest in subjects reporting no physical activity, and low adherence to Mediterranean diet. In the NAFLD group, weight gain occurred in 70% of cases. Subjects reporting weight loss during lockdown had decreased fatty liver score at 3 months before the lockdown, as compared with 1 year before. CONCLUSIONS: Strict measures of social containment-even short-term-pave the way to the increased risk of metabolic abnormalities in the medium-long term. In this context, adherence to Mediterranean diet and regular physical activity play a protective role both in terms of weight gain and fatty liver development/progression, with implication for primary and secondary prevention. When adopting measures imposing social containment, intensive educational campaigns must increase public awareness about beneficial effects of healthy lifestyles.


Assuntos
COVID-19 , Dieta/estatística & dados numéricos , Exercício Físico , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Obesidade/metabolismo , Ganho de Peso , Adolescente , Adulto , Controle de Doenças Transmissíveis , Dieta Mediterrânea , União Europeia , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Sobrepeso/metabolismo , Política Pública , SARS-CoV-2 , Inquéritos e Questionários , Adulto Jovem
14.
Eur J Clin Invest ; 51(7): e13597, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: covidwho-1242159

RESUMO

BACKGROUND: Social containment measures imposed in Europe during the lockdown to face COVID-19 pandemic can generate long-term potential threats for metabolic health. METHODS: A cohort of 494 non-COVID-19 subjects living in 21 EU countries were interviewed by an anonymous questionnaire exploring anthropometric and lifestyle changes during 1-month lockdown. A subgroup of 41 overweight/obese Italian subjects with previously diagnosed nonalcoholic fatty liver (NAFLD) joined the study following a 12-month follow-up period promoting weight loss by healthy lifestyle. RESULTS: During the lockdown, body weight increased in 55% of subjects (average 2.4 ± 0.9 kg). Weight change increased with age, but not baseline body mass index. Subjects living in Italy had greater weight gain than those living in other European Countries. Weight gain during the lockdown was highest in subjects reporting no physical activity, and low adherence to Mediterranean diet. In the NAFLD group, weight gain occurred in 70% of cases. Subjects reporting weight loss during lockdown had decreased fatty liver score at 3 months before the lockdown, as compared with 1 year before. CONCLUSIONS: Strict measures of social containment-even short-term-pave the way to the increased risk of metabolic abnormalities in the medium-long term. In this context, adherence to Mediterranean diet and regular physical activity play a protective role both in terms of weight gain and fatty liver development/progression, with implication for primary and secondary prevention. When adopting measures imposing social containment, intensive educational campaigns must increase public awareness about beneficial effects of healthy lifestyles.


Assuntos
COVID-19 , Dieta/estatística & dados numéricos , Exercício Físico , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Obesidade/metabolismo , Ganho de Peso , Adolescente , Adulto , Controle de Doenças Transmissíveis , Dieta Mediterrânea , União Europeia , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Sobrepeso/metabolismo , Política Pública , SARS-CoV-2 , Inquéritos e Questionários , Adulto Jovem
15.
Clin Nutr ESPEN ; 43: 329-334, 2021 06.
Artigo em Inglês | MEDLINE | ID: covidwho-1193265

RESUMO

BACKGROUND & AIMS: Given reports of changes in dietary habits during covid-19 lockdown, our aim was to assess weight changes, over a 3-month Covid-19 national lockdown in a cohort of NAFLD-HIV patients on a dietary intervention trial. METHODS: After NAFLD screening in an outpatient Infectious Diseases Clinic, NAFLD patients were randomly allocated to general dietary recommendations (SC group) or to a structured dietary intervention based on the Mediterranean diet (intervention group). During lockdown, follow-up consultations in the intervention group were done by video and/or phone. After 3 months of lockdown, all patients (intervention and SC group) consented to a telephone interview which aimed to characterize eating habits and lifestyle changes and evaluate stress and depression. Biochemical data when available, was compared between the peri-period of confinement. RESULTS: One hundred and twelve patients were screened. From the 55 NAFDL identified, 27 were allocated to dietary intervention and 28 to SC and were followed before lockdown for a mean period of 5.0 ± 1.5 months in which SC group gained a median of 0.65 kg vs. a median loss of 1.5 kg in the intervention group (p < 0.001). During lockdown, 93.3% of patients in the SC group referred that "diet got worse" vs. 6.7% in the intervention group p < 0.01), and 35.3% vs. 15.7% (p = 0.014) reported increase in appetite, respectively. Both groups gained weight, SC group vs. 0.7 ± 1.7 kg in the intervention group, p < 0.001). Higher weight gain was associated with changes in the dietary pattern (3.8 ± 2.1 kg vs. 2.0 ± 1.3 kg in "no change in dietary pattern"; p = 0.002). Glucose blood levels increased after lockdown in the SC group, with a mean increase of 15 mg/dl (p = 0.023). The remaining metabolic parameters remained unchanged. CONCLUSION: The maintenance of dietary intervention, using telemedicine, can mitigate the adverse change in dietary habits and physical activity pattern, preventing a substantial increase in body weight.


Assuntos
Peso Corporal , COVID-19 , Dieta Mediterrânea , Infecções por HIV/dietoterapia , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Distanciamento Físico , Telemedicina , Adulto , Apetite , Glicemia/metabolismo , COVID-19/complicações , COVID-19/prevenção & controle , COVID-19/psicologia , Controle de Doenças Transmissíveis , Depressão , Comportamento Alimentar/psicologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Pandemias , SARS-CoV-2 , Isolamento Social/psicologia , Estresse Psicológico , Ganho de Peso , Perda de Peso
16.
Food Funct ; 12(9): 4021-4033, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977946

RESUMO

Docosahexaenoic acid-enriched phosphatidylserine (DHA-PS) has attracted increasing attention because of its unique health benefits. In this study, DHA-PS was biosynthesized from DHA-enriched phosphatidylcholine (DHA-PC), which was extracted from herring roe, Clupea harengus. The ameliorating effect of DHA-PS on high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) was investigated using a mouse model. The DHA-PS treatment ameliorated NAFLD and effectively decreased the serum total cholesterol, triglyceride, non-esterified fatty acid, and low-density lipoprotein cholesterol levels and considerably increased the serum high-density lipoprotein cholesterol levels. Moreover, the DHA-PS treatment reduced the levels of liver-function enzymes and pro-inflammatory cytokines and also the oxidative stress indices. Furthermore, DHA-PS increased the diversity and richness of the beneficial intestinal microorganisms, suggesting its potential as a dietary supplement and functional food to combat HFD-induced NAFLD.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/terapia , Fosfatidilserinas/administração & dosagem , Tecido Adiposo , Animais , Peso Corporal , Disbiose/terapia , Dislipidemias , Alimento Funcional , Microbioma Gastrointestinal , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
17.
Food Funct ; 12(9): 3898-3918, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977953

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease. Dietary supplementation has become a promising strategy for managing NAFLD. Hesperetin, a citrus flavonoid, is mainly found in citrus fruits (oranges, grapefruit, and lemons) and possesses multiple pharmacological properties, including anti-cancer, anti-Alzheimer and anti-diabetic effects. However, the anti-NAFLD effect and mechanisms of hesperetin remain unclear. In this study, we investigated the therapeutic effect of hesperetin against NAFLD and the underlying mechanism in vitro and in vivo. In oleic acid (OA)-induced HepG2 cells, hesperetin upregulated antioxidant levels (SOD/GPx/GR/GCLC/HO-1) by triggering the PI3 K/AKT-Nrf2 pathway, alleviating OA-induced reactive oxygen species (ROS) overproduction and hepatotoxicity. Furthermore, hesperetin suppressed NF-κB activation and reduced inflammatory cytokine secretion (TNF-α and IL-6). More importantly, we revealed that this anti-inflammatory effect is attributed to reduced ROS overproduction by the Nrf2 pathway, as pre-treatment with Nrf2 siRNA or an inhibitor of superoxide dismutase (SOD) or/and glutathione peroxidase (GPx) abolished hesperetin-induced NF-κB inactivation and reductions in inflammatory cytokine secretion. In a rat model of high-fat diet (HFD)-induced NAFLD, we confirmed that hesperetin relieved hepatic steatosis, oxidative stress, inflammatory cell infiltration and fibrosis. Moreover, hesperetin activated the PI3 K/AKT-Nrf2 pathway in the liver, increasing antioxidant expression and inhibiting NF-κB activation and inflammatory cytokine secretion. In summary, our results demonstrate that hesperetin ameliorates hepatic oxidative stress through the PI3 K/AKT-Nrf2 pathway and that this antioxidative effect further suppresses NF-κB-mediated inflammation during NAFLD progression. Thus, our study suggests that hesperetin may be an effective dietary supplement for improving NAFLD by suppressing hepatic oxidative stress and inflammation.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Hepatócitos/efeitos dos fármacos , Hesperidina/farmacologia , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Elementos de Resposta Antioxidante , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Interleucina-6/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Ácido Oleico/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Ativação Transcricional , Fator de Necrose Tumoral alfa/metabolismo
18.
Clin Nutr ESPEN ; 43: 329-334, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34024536

RESUMO

BACKGROUND & AIMS: Given reports of changes in dietary habits during covid-19 lockdown, our aim was to assess weight changes, over a 3-month Covid-19 national lockdown in a cohort of NAFLD-HIV patients on a dietary intervention trial. METHODS: After NAFLD screening in an outpatient Infectious Diseases Clinic, NAFLD patients were randomly allocated to general dietary recommendations (SC group) or to a structured dietary intervention based on the Mediterranean diet (intervention group). During lockdown, follow-up consultations in the intervention group were done by video and/or phone. After 3 months of lockdown, all patients (intervention and SC group) consented to a telephone interview which aimed to characterize eating habits and lifestyle changes and evaluate stress and depression. Biochemical data when available, was compared between the peri-period of confinement. RESULTS: One hundred and twelve patients were screened. From the 55 NAFDL identified, 27 were allocated to dietary intervention and 28 to SC and were followed before lockdown for a mean period of 5.0 ± 1.5 months in which SC group gained a median of 0.65 kg vs. a median loss of 1.5 kg in the intervention group (p < 0.001). During lockdown, 93.3% of patients in the SC group referred that "diet got worse" vs. 6.7% in the intervention group p < 0.01), and 35.3% vs. 15.7% (p = 0.014) reported increase in appetite, respectively. Both groups gained weight, SC group vs. 0.7 ± 1.7 kg in the intervention group, p < 0.001). Higher weight gain was associated with changes in the dietary pattern (3.8 ± 2.1 kg vs. 2.0 ± 1.3 kg in "no change in dietary pattern"; p = 0.002). Glucose blood levels increased after lockdown in the SC group, with a mean increase of 15 mg/dl (p = 0.023). The remaining metabolic parameters remained unchanged. CONCLUSION: The maintenance of dietary intervention, using telemedicine, can mitigate the adverse change in dietary habits and physical activity pattern, preventing a substantial increase in body weight.


Assuntos
Peso Corporal , COVID-19 , Dieta Mediterrânea , Infecções por HIV/dietoterapia , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Distanciamento Físico , Telemedicina , Adulto , Apetite , Glicemia/metabolismo , COVID-19/complicações , COVID-19/prevenção & controle , COVID-19/psicologia , Controle de Doenças Transmissíveis , Depressão , Comportamento Alimentar/psicologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Pandemias , SARS-CoV-2 , Isolamento Social/psicologia , Estresse Psicológico , Ganho de Peso , Perda de Peso
19.
Nat Commun ; 12(1): 3059, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031390

RESUMO

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, however, no drug treatment has been approved for this disease. Thus, it is urgent to find effective therapeutic targets for clinical intervention. In this study, we find that liver-specific knockout of PPDPF (PPDPF-LKO) leads to spontaneous fatty liver formation in a mouse model at 32 weeks of age on chow diets, which is enhanced by HFD. Mechanistic study reveals that PPDPF negatively regulates mTORC1-S6K-SREBP1 signaling. PPDPF interferes with the interaction between Raptor and CUL4B-DDB1, an E3 ligase complex, which prevents ubiquitination and activation of Raptor. Accordingly, liver-specific PPDPF overexpression effectively inhibits HFD-induced mTOR signaling activation and hepatic steatosis in mice. These results suggest that PPDPF is a regulator of mTORC1 signaling in lipid metabolism, and may be a potential therapeutic candidate for NAFLD.


Assuntos
Fígado Gorduroso/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Proteínas Culina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Metabolismo dos Lipídeos , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo
20.
Medicine (Baltimore) ; 100(21): e26043, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032730

RESUMO

BACKGROUND: T2DM with NAFLD is a common disorder of glucose and lipid metabolism affecting the quality of life of patients. Due to the limitations and adverse reactions of drug treatment, acupuncture has been proved to be an effective method for the treatment of T2DM with NAFLD. This study aims to evaluate the efficacy and safety of acupuncture in the treatment of NAFLD in T2DM class, and to provide high-quality evidence for acupuncture in the treatment of this disease. METHODS: From establishment of the database to 31 July 2021, We will search the Cochrane Central Register of controlled trials, PubMed, MEDLINE, EMBASE, Web of science. Five Chinese databases, including China National Knowledge Infrastructure (CNKI), WanFang database, VIP, Chinese Biomedical Literature Database (CBM) and the Chinese clinical trial registry. There are no restrictions on language or publication, and they are independently screened and collected by two reviewers. Review Manager 5.3 software will be used for meta analysis. If necessary, heterogeneity testing, data synthesis, and subgroup analysis will be performed. RESULTS: The effectiveness and safety of acupuncture in the treatment of T2DM with NAFLD will be assessed by the outcomes of test's, including: imaging indicators, biomarkers of hepatic steatosis, serological indicators of hepatic fibrosis, improvement of serum NAFLD liver fat score, BMI, blood glucose indexes, blood lipid indexes, insulin level and safety indicators. CONCLUSION: This meta-analysis will further determine the beneficial efficacy and safety of acupuncture for T2DM combined with NAFLD.


Assuntos
Terapia por Acupuntura/métodos , Diabetes Mellitus Tipo 2/terapia , Hepatopatia Gordurosa não Alcoólica/terapia , Terapia por Acupuntura/efeitos adversos , Biomarcadores/sangue , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Metanálise como Assunto , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto , Resultado do Tratamento
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