Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of abnormal liver function in countries with western-style high fat, high cholesterol diets. Liver damage associated with NAFLD may lead to liver cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). Additionally, recent data suggest that nonalcoholic steatohepatitis (NASH), the inflammatory phase of NAFLD, is linked to increased cardiovascular risk independent of the broad spectrum of risk factors of metabolic syndrome. Therefore, novel therapies are needed to inhibit the inflammatory liver damage that drives NAFLD. Hepatic macrophages (HMΦ’s), which include resident Kupffer cells and monocyte-derived macrophages, are the primary drivers of liver inflammation in both human and mouse models. In macrophages, chronic lipid exposure promotes pro-inflammatory polarization and the activation of pyroptosis via the NLRP3 inflammasome. While the role of the canonical pyroptosis pathway has been studied in NAFLD, the role of the newly discovered noncanonical (caspase-11/-Gasdermin-Ddependent) pathway has not been defined. Diet-induced NAFLD promoted hepatic steatosis and lobular inflammation in male WT mice. Caspase-11 deficiency decreases macrovesicular steatosis and total NAFLD Activity Score (NAS). High fat feeding promoted recruitment and activation of HMΦ in both Caspase-11 deficient (Casp11KO) and WT male mice, however, noncanonical pyroptosis (caspase-11 activity, surface Gasdermin-D, expression, liver IL-1β secretion) was ablated in HMΦs from Casp11KO mice. Bone marrow transplantation restored capacity for noncanonical pyroptosis in Casp11KO mice. RNAseq and microarray analysis revealed that lipid peroxidation and trained immunity mediate noncanonical pyroptosis in diet induced NALFD. / Biomedical Sciences / Accompanied by 1 PDF file: DrummerIV_temple_0225E_171/CED

No description available.

Obesity is a prevalent disease in which, when compared to individuals of normal weight, obese individuals have noted pathophysiological alterations including increased adiposity and fat mass which may alter toxicokinetics of xenobiotics and therefore alter their toxicities. However, the effects of obesity and the altered pathophysiology accompanying this condition on the toxicity of many widely utilized pesticides have not been established. Organophosphate (OP) pesiticides, including chlorpyrifos (CPS), have historically been widely used for agricultural purposes. CPS and several other notable OPs are no longer registered for household use but still used mainly in agriculture by registered users. CPS is bioactivated to form chlorpyrifos-oxon (CPO) in liver by cytochrome P450 isozymes. Acute toxicity of CPS exposure is inhibition of acetylcholinesterase (AChE) in the central and peripheral nervous systems. The other targets following CPS exposure are the noncholinergic serine hydrolase enzymes: carboxylesterase (CES), fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MAGL). Therefore the current study was designed to: 1) determine the time and concentration-dependent effects of CPS on noncholinergic endpoints of OP toxicity utilizing hepatoma cells under normal and steatotic conditions 2) determine if obese phenotype altered the toxicity of CPS, including both cholinergic and non-cholinergic endpoints and 3) determine the effects of high fat diet on CPS bioaccumulation and detoxication by determining CPS and 3,5,6-trichloro-2-pyridinol (TCP) levels at different time points. The current in vitro studies determined that CES is more sensitive to CPS mediated inhibition in normal and steatotic conditions compared to FAAH and MAGL. The in vivo studies determined that CPS (2 mg/kg) exposure produced a greater inhibitory effect on hepatic CES and FAAH in obese animals compared to lean animals which indicates that the obese animals may be at greater risk for CPS mediated alterations in hepatic lipid metabolism upon chronic exposure. Our toxicokinetic studies using a higher dose of CPS (25 mg/kg) did not inhibit AChE in CNS and did not alter the overall CPS levels between normal and obese animals. Peak levels of TCP were decreased in liver of obese animals at 3 hours and overall hepatic TCP levels were significantly decreased in obese animals.

No description available.

Non-alcoholic fatty liver disease (NAFLD) is a major chronic liver disease and thus a main reason for liver-related morbidities and mortality. NAFLD covers a wide range of diseases starting with steatosis and frequently progressing to non-alcoholic steatohepatitis (NASH), which is an independent predictor for the development of the hepatocellular carcinoma (HCC). Nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme of the mammalian NAD salvage pathway, recycles nicotinamide to nicotinamide mononucleotide (NMN), which is further converted to nicotinamide adenine dinucleotide (NAD). NAD is not only an important redox partner but also a crucial co-substrate for NAD-dependent enzymes such as sirtuin 1 (SIRT1). Thus, NAD metabolism might be involved in the progression of NAFLD by regulating many cellular processes, such as apoptosis, de novo lipogenesis, glycolysis and gluconeogenesis, in the liver. Interestingly, tumor cells have a high NAD turnover due to their rapid proliferation and high activity of NAD-dependent enzymes. For these reasons, I hypothesized that the NAD salvage pathway is dysregulated during the progression of non-alcoholic fatty liver disease. Therefore, the first study of the present work deals with the role of the NAD salvage pathway in a diet-induced mouse model of hepatic steatosis. In mice fed a high-fat diet for 11 weeks hepatic NAMPT mRNA, protein abundance and activity as well as NAD levels were increased. Additionally, SIRT1 protein abundance was upregulated indicating a higher SIRT1 activity. This could be confirmed by detecting decreased acetylation or transcription of SIRT1 targets. For example, p53 and nuclear factor κB (NF-κB) were less acetylated demonstrating lower activity of key regulators of apoptosis and inflammation, respectively. In the second study of this thesis NAMPT activity was inhibited by applying its specific inhibitor FK866 in hepatocarcinoma cells to investigate whether or not NAMPT inhibition could be a potential novel therapeutic approach in HCC treatment. Hepatocarcinoma cells were more sensitive to NAMPT inhibition by FK866 than primary human hepatocytes, presenting a high number of apoptotic cells after FK866 treatment. FK866 induced NAD and ATP depletion which was associated with activation of the key regulator of energy metabolism 5’-AMP-activated protein kinase (AMPK) and decreased activity of its downstream target mammalian target of rapamycin (mTOR). This thesis shows that the NAD salvage pathway is involved in hepatic steatosis and HCC. During hepatic steatosis NAD metabolism is upregulated to potentially protect against adverse effects of the massive hepatic lipid accumulation. To repress the progression to NASH it might be useful to maintain the hepatic NAD levels during early disease stages by administration of NAD precursors, such as NMN. However, hepatocarcinoma cells have a higher activity of NAMPT and NAD-dependent enzymes. NAMPT inhibition by FK866 could be a potential therapeutic approach in HCC, especially due to the fact that NAD depletion is selectively induced in hepatocarcinoma cells, but not in primary human hepatocytes.

Chez les mammiferes, la lipogenese ou synthese de novo des acides gras joue un rôle essentiel a l'homeostasie energetique. Elle est particulierement active dans le foie. Le Liver X Receptor (LXR) est un recepteur nucleaire de classe II qui est implique dans la regulation de l'expression de genes importants dans cette voie metabolique. Au niveau hepatique, LXR regule directement l'expression de certains genes de la lipogenese et aussi l'expression des facteurs de transcription SREBP-1c et ChREBP intervenant respectivement dans la reponse hepatique a l'insuline et au glucose. Les ligands naturels de LXR sont les oxysterols, des derives oxygenes du cholesterol. Aussi, LXR est avant tout considere et connu comme un senseur du cholesterol. Au cours de ces travaux nous nous sommes interesses in vivo au role de LXR dans la regulation transcriptionnelle de la lipogenese hepatique en fonction de differents stimuli: pharmacologiques, inflammatoires et nutritionnels. Par une approche pharmacologique, nous avons etudie la regulation croisee avec entre LXR et le recepteur active par les proliferateurs de peroxisome (PPAR . Nous avons aussi montre que l'inflammation intestinale est un puissant inhibiteur de la lipogenese hepatique. Enfin, nous avons mis en evidence le role de LXR dans la regulation de la lipogenese en reponse a une carence en acides gras essentiels et a un regime riche en fructose. / In mammals, lipogenesis or de novo fatty acid synthesis plays an essential part in energy homeostasis. It is particularly active in the liver. The Liver X Receptor (LXR) is a class II nuclear receptor that regulates the expression of important genes involved in this pathway. In the liver, LXR directly controls the expression of lipogenic genes and also the expression of transcription factors such as SREBP-1c and ChREBP required for the hepatic response to insulin and glucose respectively. Natural ligands for LXR are oxysterols, which are oxygenated derivatives of cholesterol. Therefore, LXR is primarily considered and known as a cholesterol sensor. In this work, we were interested in the role of LXR in the transcriptional control of hepatic lipogenesis in vivo in response to distinct stimuli: pharmacological agonists, gut inflammation and changes in diet composition. Through a pharmacological study, we highlighted the cross-talk between LXR signaling and the regulation of the Peroxisome Proliferator Activated Receptor (PPAR ). We have also evidenced that experimentally induced colitis induces a potent inhibition of hepatic lipogenesis. Finally, we have shown that LXR is involved in the regulation of lipogenesis in response to essential fatty acid deficiency and to high fructose.

O câncer é um dos principais problemas de saúde pública no mundo. Dentre as neoplasias primárias que acometem o fígado, o carcinoma hepatocelular (HCC) é a mais frequente. Diversos fatores de risco predispõem ao HCC, entre eles a doença hepática gordurosa não-alcoólica (NAFLD). Segundo estudos prévios do grupo, a &#946;-ionona (BI), presente em uvas e aromatizantes de vinho, apresenta potencial quimiopreventivo da hepatocarcinogênese. Além disso, a &#946;I parece atuar na redução da colesterolemia podendo, assim, influenciar a NAFLD. Desta forma pretendeu-se, neste projeto, avaliar o desenvolvimento da NAFLD e sua influência nas etapas de iniciação e seleção/promoção da hepatocarcinogênese em ratos Wistar submetidos ao modelo do hepatócito resistente (RH), além da atividade quimiopreventiva da &#946;I, nessas condições experimentais em ratos. Para isso, os animais foram alocados em 6 grupos experimentais: RH iniciação (n=11), NAFLD iniciação (n=15), BI iniciação (n=15), RH seleção/promoção (n=11), NAFLD seleção promoção (n=15) e BI seleção/promoção (n=15). Na fase de iniciação os animais do grupo NAFLD receberam, diariamente, emulsão hipercalórica até a sexta semana do experimento um dia antes da administração de DEN. Já na fase de seleção/promoção os animais do grupo NAFLD receberam a emulsão hipercalórica, a partir de um dia após a DEN. Os animais dos grupos RH da iniciação e da seleção/promoção servem como controles e receberam, diariamente, 1mL/100g peso corpóreo de água até a sexta semana do experimento e um dia após a DEN, respectivamente. Na fase de iniciação, após 13 semanas os animais do grupo NAFLD não demonstraram sinais de esteatose, apresentaram maiores níveis séricos de triacilglicerol, colesterol total e LDL comparados ao grupo RH (P<0,05). O grupo NAFLD apresentou maior porcentagem de nódulos macroscópicos, bem como maior número e porcentagem de área hepática de lesões pré neoplásicas persistentes (pLPN) comparado ao grupo RH (P<0,05). Já o grupo BI apresentou menor número de pLPN e maior número de lesões em remodelação e uma maior porcentagem de área hepática de rLPN (p<0,05). Em relação a proliferação celular, o grupo NAFLD apresentou maior número de células em sourrounding, pLPN e rLPN comparada ao grupo RH e o grupo BI menor número em pLPN comparada a NAFLD. Já na fase de seleção/promoção foi possível observar o grupo NAFLD tem maiores valores de focos de inflamação, hepatócitos balonizados e grau de esteatose hepática em relação ao grupo BI, assim como maiores níveis séricos de triacilgliceróis, colesterol total e LDL (p<0,05). O grupo NAFLD apresentou maior porcentagem de nódulos macroscópicos <1, maior número, menor tamanho médio de pLPN comparados ao grupo RH (p<0,05). O grupo BI apresentou menor número e menor porcentagem de área em pLPN e maior porcentagem de área em rLPN (p<0,05). Em relação a proliferação celular, o grupo NAFLD apresentou maior número de células em sourrounding, pLPN e rLPN comparada ao grupo RH (p<0,05). Na expressão gênica, o grupo BI apresentou maior expressão de HMGCR em relação grupo NAFLD (p<0,05), O grupo NAFLD apresentou maior expressão de INSIG1 em relação ao grupo RH (p<0,05) e tendência na expressão de INSIG 2. / Cancer is a major public health problems in the world. Among the primary neoplasm affecting the liver, hepatocellular carcinoma (HCC) is the most frequent. Several risk factors predispose to HCC, including the non-alcoholic fatty liver disease (NAFLD). According to previous studies of the group, &#946;-ionone (BI), present in grapes and flavors of wine, it presents potential chemopreventive of hepatocarcinogenesis. Furthermore, &#946;I appears to act in reducing blood cholesterol and may thus influence NAFLD. In this way it was intended in this project, evaluate the development of NAFLD and its influence on the steps of initiation and selection/promotion of hepatocarcinogenesis in Wistar rats resistant hepatocyte model (HR), and the chemopreventive activity of &#946;I, these experimental conditions in rats. For this, the animals were divided into 6 groups: RH initiation (n = 11), NAFLD initiation (n = 15), BI initiation (n = 15), HR selection / promotion (n = 11), NAFLD selection promotion ( n = 15) and BI selection / promotion (n = 15). In the inception phase of the NAFLD group animals received daily calorie emulsion until the sixth week of the experiment one day prior to DEN administration. In the selection / promotion stage NAFLD group of animals received hypercaloric emulsion, from one day after the DEN. The animals of groups HR and selection of initiation / promotion serve as controls and received daily 1mL / 100g body weight of water until the sixth week of the experiment, and one day after DEN respectively. In the initiation phase, after 13 weeks the animals of group NAFLD showed no signs steatosis, had higher serum levels of triglyceride, total cholesterol and LDL compared to the HR group (P <0.05). The NAFLD showed higher prevalence of macroscopic nodules as well as higher number and percentage of liver area of persistent pre-neoplastic lesions (pLPN) compared to the HR group (P <0.05). But the BI group had fewer pLPN and higher number of lesions in remodeling and a higher percentage of liver area rLPN (p <0.05). In relation to cell proliferation, the NAFLD group had a higher number of cells in sourrounding, pLPN and rLPN compared to the RH group and the lowest number in pLPN BI group compared to NAFLD. In the selection / promotion layer was observed NAFLD group has the highest values of inflammation foci, balonizados hepatocytes and hepatic steatosis grade in relation to BI group as well as higher serum levels of triglyceride, total cholesterol and LDL (p <0 , 05). The NAFLD showed higher prevalence of macroscopic nodules <1, more, smaller average size pLPN compared to the HR group (p <0.05). The BI group had fewer and smaller percentage area in pLPN and higher percentage of area rLPN (p <0.05). In relation to cell proliferation, the NAFLD group had a higher number of cells in sourrounding, pLPN and rLPN compared to the HR group (p <0.05). In gene expression, the BI group showed higher expression of HMGCR regarding NAFLD group (p <0.05), the NAFLD group had higher expression of INSIG1 against the RH group (p <0.05) and a tendency in the expression of INSIG 2.

L'obésité, un problème de santé mondial, est associée à des comorbidités telles que le syndrome métabolique, la stéato-hépatite non alcoolique, la cardiomyopathie métabolique etc. Leur incidence et développement peuvent être le résultat des interactions gènes-environnement. Ces dernières années, une série d’études expérimentales et cliniques ont montré l’implication de donneurs de méthyles dans ces pathologies via la programmation fœtale. Notre travail a évalué, à la fois le rôle de donneurs de méthyles et le profil métabolique dans une population d’obèses, puis sur un modèle animal de ratons avec une carence en donneurs de méthyles, soumis à la vie adulte à un régime hyper-énergétique. Chez l’homme, nous avons démontré qu’une carence en vitamine B12 associée à un excès de folates est liée à l’insulino-résistance. Puis, nous avons observé des anomalies du métabolisme des acides gras. Chez l’animal, nous avons montré que la carence en donneurs de méthyles provoque une hypertension artérielle systémique et une fibrose cardiaque, surtout chez les femelles. Par contre, chez les mâles, nous avons observé une stéatose hépatique dans le groupe des rats mâles carencés et soumis à un régime hyper-énergétique. En conclusion, la carence en donneurs de méthyles est associée aux maladies chronico-dégénératives. / Obesity, is global health problem, is associated with comorbidities such as metabolic syndrome, nonalcoholic steatohepatitis, metabolic cardiomyopathy etc. Their incidence and development may be the result of gene-environment interactions. In the last years, the experimental and clinical studies have shown the involvement of methyl donors in these pathologies via « fetal programming ». Our work has evaluated the role of methyl donor on metabolic profile in obese subjects, and also in an animal model of pups with a deficiency of methyl donors, subject to high-fat diet in adulthood. In humans, we have demonstrated that vitamin B12 deficiency associated with excess in folates, is linked to insulin resistance. Also the methyl donors have an influence on fatty acid metabolism. In animals, we have shown that deficiency of methyl donors causes systemic hypertension and cardiac fibrosis, especially in females. In contrast, the males methyl donor deficient with a high fat diet had an important steatosis. In conclusion, the methyl donor shortage is associated with chronic degenerative diseases.

O ácido palmitoleico (POA) é descrito como uma lipocina, capaz de melhorar a responsividade à insulina, estimular a oxidação de lipídios e reduzir a inflamação, efeitos essenciais para o controle da doença do fígado gorduroso não alcoólico (NAFLD). Assim, investigamos se o POA pode proteger contra os efeitos deletérios de uma dieta rica em gordura saturada (HF-L) ou gordura trans (HF-T), verificando a participação de PPAR&#945; e PPAR&#947;. Para tanto utilizamos camundongos selvagens alimentados com uma dieta padrão (SD), ou animais knockout total de PPAR&#945; (PPAR&#945;KO) ou com deleção de PPAR&#947; em células mielóides (PPAR&#947;KOLyzCre+) alimentados com HF. As dietas foram administradas por 12 semanas, e a partir da 10ª semana os animais foram suplementados com ácido oleico ou POA (300mg/kg). Utilizamos também macrófagos intraperitoneais extraídos de animais WT, PPAR&#945;KO e PPAR&#947;KOLyzCre+ alimentados com SD com LPS ou LPS + POA (600uM). A HF promoveu resistência à insulina, esteatose e inflamação exacerbada no fígado dos animais, independente do genótipo. Embora não tenha reduzido o acúmulo ectópico de lipídios no fígado, ou modulado a expressão de fatores lipogênicos, POA melhorou a resposta à insulina periférica e hepática. No fígado, POA não modulou fatores da cascata de insulina, ou a produção de adiponectina, porém, estimulou a ativação de AMPK e aumentou os níveis FGF-21, de forma dependente de PPAR&#945;. POA reduziu a inflamação hepática, por diminuir TLR4, NF&#954;B e fatores do inflamassoma, mas principalmente, por inibir a polarização de macrófagos do fígado para o fenótipo M1, um efeito que ocorreu mesmo em animais PPAR&#947;KOLyzCre+, apesar da maior expressão gênica e proteica de PPAR&#947; observada em macrófagos com POA, in vivo e in vitro. Nossos dados indicam que o POA promove efeitos benéficos contra intolerância à glicose e resistência à insulina hepática e periférica induzida por dieta rica em gordura, por ativação de AMPK, FGF21 e PPAR&#945;. E, por reduzir a polarização M1 de macrófagos, independente de PPARs, este ácido graxo 16:1n-7 é capaz de reduzir a inflamação no fígado induzida por dieta hiperlipídica. / Palmitoleic acid (POA) is described as a lipokine, capable of improving insulin responsiveness, stimulating lipid oxidation and reducing inflammation, essential for the control of non-alcoholic fatty liver disease (NAFLD). Thus, we investigated whether POA can protect against the deleterious effects of a diet rich in saturated fat (HF-L) or trans fat (HF-T), verifying the role of PPAR&#945; and PPAR&#947;. We used wild-type mice fed a standard diet (SD), or whole-body PPAR&#945; knockout (PPAR&#945;KO) mice or mice with myeloid cells selective-delected PPAR&#947; (PPAR&#947;KOLyzCre+) fed a HF. The diets were administered for 12 weeks, and from the 10th week the animals were supplemented with oleic acid or POA (300mg/kg). Intraperitoneal macrophages extracted from WT, PPAR&#945;KO and PPAR&#947;KOLyzCre+ mice fed SD and stimulated with LPS or LPS+POA (600&#956;M), were also analyzed. HF promoted insulin resistance, steatosis and exacerbated inflammation in the liver of mice, regardless of genotype. Although it did not reduce the lipids ectopic accumulation in the liver, or modulated the lipogenic factors expression, POA improved the peripheral and hepatic insulin response. In the liver, POA did not modulate factors of the insulin cascade, or adiponectin production, however, stimulated AMPK activation and increased FGF-21 levels, in a PPAR&#945;-dependent manner. POA reduced liver inflammation by decreasing TLR4, NF&#954;B and inflammatory factors, but mainly by inhibiting the macrophage polarization of the liver to the M1 phenotype, an effect that occurred even in PPAR&#947;KOLyzCre+ mice, despite the increased gene and protein expression of PPAR&#947; observed in macrophages with POA, in vivo and in vitro. Our data indicate that the POA promotes beneficial effects against glucose intolerance and hepatic and peripheral insulin resistance induced by a high fat diet through the activation of AMPK, FGF21 and PPAR&#945;. And, by reducing the M1 polarization of macrophages, independent of PPARs, this 16: 1n-7 fatty acid is able to reduce inflammation in the liver induced by high fat diet.

O câncer é um dos principais problemas de saúde pública no mundo. Dentre as neoplasias primárias que acometem o fígado, o carcinoma hepatocelular (HCC) é a mais frequente. Diversos fatores de risco predispõem ao HCC, entre eles a doença hepática gordurosa não-alcoólica (NAFLD). Segundo estudos prévios do grupo, a &#946;-ionona (BI), presente em uvas e aromatizantes de vinho, apresenta potencial quimiopreventivo da hepatocarcinogênese. Além disso, a &#946;I parece atuar na redução da colesterolemia podendo, assim, influenciar a NAFLD. Desta forma pretendeu-se, neste projeto, avaliar o desenvolvimento da NAFLD e sua influência nas etapas de iniciação e seleção/promoção da hepatocarcinogênese em ratos Wistar submetidos ao modelo do hepatócito resistente (RH), além da atividade quimiopreventiva da &#946;I, nessas condições experimentais em ratos. Para isso, os animais foram alocados em 6 grupos experimentais: RH iniciação (n=11), NAFLD iniciação (n=15), BI iniciação (n=15), RH seleção/promoção (n=11), NAFLD seleção promoção (n=15) e BI seleção/promoção (n=15). Na fase de iniciação os animais do grupo NAFLD receberam, diariamente, emulsão hipercalórica até a sexta semana do experimento um dia antes da administração de DEN. Já na fase de seleção/promoção os animais do grupo NAFLD receberam a emulsão hipercalórica, a partir de um dia após a DEN. Os animais dos grupos RH da iniciação e da seleção/promoção servem como controles e receberam, diariamente, 1mL/100g peso corpóreo de água até a sexta semana do experimento e um dia após a DEN, respectivamente. Na fase de iniciação, após 13 semanas os animais do grupo NAFLD não demonstraram sinais de esteatose, apresentaram maiores níveis séricos de triacilglicerol, colesterol total e LDL comparados ao grupo RH (P<0,05). O grupo NAFLD apresentou maior porcentagem de nódulos macroscópicos, bem como maior número e porcentagem de área hepática de lesões pré neoplásicas persistentes (pLPN) comparado ao grupo RH (P<0,05). Já o grupo BI apresentou menor número de pLPN e maior número de lesões em remodelação e uma maior porcentagem de área hepática de rLPN (p<0,05). Em relação a proliferação celular, o grupo NAFLD apresentou maior número de células em sourrounding, pLPN e rLPN comparada ao grupo RH e o grupo BI menor número em pLPN comparada a NAFLD. Já na fase de seleção/promoção foi possível observar o grupo NAFLD tem maiores valores de focos de inflamação, hepatócitos balonizados e grau de esteatose hepática em relação ao grupo BI, assim como maiores níveis séricos de triacilgliceróis, colesterol total e LDL (p<0,05). O grupo NAFLD apresentou maior porcentagem de nódulos macroscópicos <1, maior número, menor tamanho médio de pLPN comparados ao grupo RH (p<0,05). O grupo BI apresentou menor número e menor porcentagem de área em pLPN e maior porcentagem de área em rLPN (p<0,05). Em relação a proliferação celular, o grupo NAFLD apresentou maior número de células em sourrounding, pLPN e rLPN comparada ao grupo RH (p<0,05). Na expressão gênica, o grupo BI apresentou maior expressão de HMGCR em relação grupo NAFLD (p<0,05), O grupo NAFLD apresentou maior expressão de INSIG1 em relação ao grupo RH (p<0,05) e tendência na expressão de INSIG 2. / Cancer is a major public health problems in the world. Among the primary neoplasm affecting the liver, hepatocellular carcinoma (HCC) is the most frequent. Several risk factors predispose to HCC, including the non-alcoholic fatty liver disease (NAFLD). According to previous studies of the group, &#946;-ionone (BI), present in grapes and flavors of wine, it presents potential chemopreventive of hepatocarcinogenesis. Furthermore, &#946;I appears to act in reducing blood cholesterol and may thus influence NAFLD. In this way it was intended in this project, evaluate the development of NAFLD and its influence on the steps of initiation and selection/promotion of hepatocarcinogenesis in Wistar rats resistant hepatocyte model (HR), and the chemopreventive activity of &#946;I, these experimental conditions in rats. For this, the animals were divided into 6 groups: RH initiation (n = 11), NAFLD initiation (n = 15), BI initiation (n = 15), HR selection / promotion (n = 11), NAFLD selection promotion ( n = 15) and BI selection / promotion (n = 15). In the inception phase of the NAFLD group animals received daily calorie emulsion until the sixth week of the experiment one day prior to DEN administration. In the selection / promotion stage NAFLD group of animals received hypercaloric emulsion, from one day after the DEN. The animals of groups HR and selection of initiation / promotion serve as controls and received daily 1mL / 100g body weight of water until the sixth week of the experiment, and one day after DEN respectively. In the initiation phase, after 13 weeks the animals of group NAFLD showed no signs steatosis, had higher serum levels of triglyceride, total cholesterol and LDL compared to the HR group (P <0.05). The NAFLD showed higher prevalence of macroscopic nodules as well as higher number and percentage of liver area of persistent pre-neoplastic lesions (pLPN) compared to the HR group (P <0.05). But the BI group had fewer pLPN and higher number of lesions in remodeling and a higher percentage of liver area rLPN (p <0.05). In relation to cell proliferation, the NAFLD group had a higher number of cells in sourrounding, pLPN and rLPN compared to the RH group and the lowest number in pLPN BI group compared to NAFLD. In the selection / promotion layer was observed NAFLD group has the highest values of inflammation foci, balonizados hepatocytes and hepatic steatosis grade in relation to BI group as well as higher serum levels of triglyceride, total cholesterol and LDL (p <0 , 05). The NAFLD showed higher prevalence of macroscopic nodules <1, more, smaller average size pLPN compared to the HR group (p <0.05). The BI group had fewer and smaller percentage area in pLPN and higher percentage of area rLPN (p <0.05). In relation to cell proliferation, the NAFLD group had a higher number of cells in sourrounding, pLPN and rLPN compared to the HR group (p <0.05). In gene expression, the BI group showed higher expression of HMGCR regarding NAFLD group (p <0.05), the NAFLD group had higher expression of INSIG1 against the RH group (p <0.05) and a tendency in the expression of INSIG 2.