The AASLD Guidelines state that treatment is indicated in prolong

The AASLD Guidelines state that treatment is indicated in prolonged hepatitis (>4 weeks of prolonged INR and hyperbilirubinemia).[297] It is important to commence antiviral therapy using NAs as soon as fulminant hepatitis B is suspected, whether it is a rapidly progressive

acute infection or acute exacerbation of the carrier state. Even after commencement of NA therapy once fulminant hepatitis has been diagnosed, it takes some time for the antiviral effect to appear, and improved outcomes are not always achieved, so antiviral therapy should be commenced before the onset of fulminant hepatic failure. The treatment of fulminant hepatitis is not directed solely at the etiological cause, but is a multidisciplinary treatment encompassing protective therapy, artificial liver support, Target Selective Inhibitor Library general care, and prevention of complications. Outcomes are generally poor for medical treatment of fulminant hepatitis B, so liver transplantation should be considered as soon as possible. A randomized controlled clinical trial of lamivudine in the treatment of severe hepatitis B (bilirubin ≥10 mg/dL, PT-INR 1.4–1.6) found that early administration of lamivudine significantly reduced the incidence of hepatic failure and mortality.[278] A retrospective study of lamivudine therapy for fulminant or severe hepatitis B with

PT-INR ≥2.0 found that 82.4% (14/17) of patients in the treated group survived and cleared HBsAg within 6 months, whereas the survival rate in the historical control group not administered lamivudine was only 20% (4/20), with a significant difference seen between groups see more (P < 0.001).[277] Other studies have demonstrated the efficacy of lamivudine in the treatment of fulminant hepatitis B, with no reports of problems with safety, such as adverse reactions.[298, 299] Although there are no clear guidelines for when to stop NA therapy, negative conversion of HBsAg is usually the indicator for treatment cessation. Administration of NAs is the mainstay of treatment of acute exacerbation of the

carrier state. The viral load is already high at the time of onset of fulminant hepatitis, by which stage a therapeutic response to NAs is unlikely, necessitating commencement of NA pheromone therapy before the onset of severe or fulminant hepatitis B. Although subject numbers were low, the “Prospective study of the efficacy of lamivudine” in patients with acute exacerbation of the carrier state, conducted by an MHLW study group, found that 71% (5/7) patients administered lamivudine when a prothrombin time declined to ≤40% died, but all patients administered lamivudine when a prothrombin time was ≥60% survived. They therefore recommended that lamivudine should be administered to patients with acute exacerbation of the carrier state without delay, before the prothrombin time goes below 60%.

These results implicate MIF and CD74 as possible

targets

These results implicate MIF and CD74 as possible

targets in the treatment of human chronic liver diseases. “
“Aim:  Several epidemiological studies suggest a beneficial effect of coffee consumption on the formation and progression of fibrogenic diseases, particularly of the liver. Recent data now point to a modulation of transforming growth Epigenetics inhibitor factor-β (TGF-β) signaling by paraxanthine (1,7-dimethylxanthine [1,7-DMX]), the demethylated primary metabolite of caffeine Methods:  Twenty adult Sprague–Dawley rats were bile duct ligated (BDL) or sham operated with or without concomitant oral 1,7-DMX (1 mM) application. Serum was investigated by standard biochemical analysis, in-house connective tissue growth factor (CTGF), enzyme linked immunosorbent assay (ELISA) or liquid chromatography-mass spectrometry analysis. Liver tissue was stained using hematoxylin-eosin (HE) and Sirius-red staining. Whole liver lysates, primary rat hepatocytes (PC) and hepatic

stellate cells (HSC) were investigated by CTGF, and total www.selleckchem.com/products/Adriamycin.html Smad2/3 Western blot analysis, CTGF reporter gene assay or an in-house malondialdehyde ELISA. Results:  The in vitro 50% inhibitory dose (ID50) of 1,7-DMX was 0.95 mM by for CTGF promoter activity and protein expression in PC and 1.25 mM for protein expression in HSC. Oral 1,7-DMX application (1 mM) attenuated cholestatic hepatocellular injury in vivo as determined either by biochemical serum analysis and reduced intercellular collagen deposition in the cholestatic rat liver (HE- and Sirius-red staining). Western Blot analysis of whole liver lysates revealed a reduction of intrahepatic concentrations of Smad2/3 and CTGF following oral 1,7-DMX intake. However, serum CTGF concentrations were not reduced

in 1,7-DMX treated BDL rats. Oral 1,7-DMX furthermore led to a reduction of intrahepatic lipid peroxidation (malondialdehyde concentrations) as markers of oxidative stress in BDL rats. Conclusion:  Our pilot study warrants further studies of 1,7-DMX as a potential new drug to fight fibrotic processes, not just of the liver. “
“Blocking bile acid absorption in the intestine is an effective approach to reducing the pool of serum bile acids (SBA). Thus, inhibiting the ileal bile acid transporter ASBT is being considered as a new treatment for cholestatic liver diseases. We report the effect of SC-435, a potent, minimally absorbed ASBT inhibitor (ASBTi) on liver function parameters in a rat partial bile duct ligation (pBDL) model of cholestasis. We adapted a previously described mouse pBDL model (Heinrich et al., Surgery 2011) to create a model in HSD rats which displays key characteristics of cholestatic liver disease – markedly elevated serum bile acids and liver function markers. Rats were anesthetized with isoflurane, the common bile duct exposed by midline laparotomy and a short length of PE-10 tubing placed parallel to the bile duct.

These results implicate MIF and CD74 as possible

targets

These results implicate MIF and CD74 as possible

targets in the treatment of human chronic liver diseases. “
“Aim:  Several epidemiological studies suggest a beneficial effect of coffee consumption on the formation and progression of fibrogenic diseases, particularly of the liver. Recent data now point to a modulation of transforming growth Pexidartinib research buy factor-β (TGF-β) signaling by paraxanthine (1,7-dimethylxanthine [1,7-DMX]), the demethylated primary metabolite of caffeine Methods:  Twenty adult Sprague–Dawley rats were bile duct ligated (BDL) or sham operated with or without concomitant oral 1,7-DMX (1 mM) application. Serum was investigated by standard biochemical analysis, in-house connective tissue growth factor (CTGF), enzyme linked immunosorbent assay (ELISA) or liquid chromatography-mass spectrometry analysis. Liver tissue was stained using hematoxylin-eosin (HE) and Sirius-red staining. Whole liver lysates, primary rat hepatocytes (PC) and hepatic

stellate cells (HSC) were investigated by CTGF, and total selleck compound Smad2/3 Western blot analysis, CTGF reporter gene assay or an in-house malondialdehyde ELISA. Results:  The in vitro 50% inhibitory dose (ID50) of 1,7-DMX was 0.95 mM by for CTGF promoter activity and protein expression in PC and 1.25 mM for protein expression in HSC. Oral 1,7-DMX application (1 mM) attenuated cholestatic hepatocellular injury in vivo as determined Idoxuridine by biochemical serum analysis and reduced intercellular collagen deposition in the cholestatic rat liver (HE- and Sirius-red staining). Western Blot analysis of whole liver lysates revealed a reduction of intrahepatic concentrations of Smad2/3 and CTGF following oral 1,7-DMX intake. However, serum CTGF concentrations were not reduced

in 1,7-DMX treated BDL rats. Oral 1,7-DMX furthermore led to a reduction of intrahepatic lipid peroxidation (malondialdehyde concentrations) as markers of oxidative stress in BDL rats. Conclusion:  Our pilot study warrants further studies of 1,7-DMX as a potential new drug to fight fibrotic processes, not just of the liver. “
“Blocking bile acid absorption in the intestine is an effective approach to reducing the pool of serum bile acids (SBA). Thus, inhibiting the ileal bile acid transporter ASBT is being considered as a new treatment for cholestatic liver diseases. We report the effect of SC-435, a potent, minimally absorbed ASBT inhibitor (ASBTi) on liver function parameters in a rat partial bile duct ligation (pBDL) model of cholestasis. We adapted a previously described mouse pBDL model (Heinrich et al., Surgery 2011) to create a model in HSD rats which displays key characteristics of cholestatic liver disease – markedly elevated serum bile acids and liver function markers. Rats were anesthetized with isoflurane, the common bile duct exposed by midline laparotomy and a short length of PE-10 tubing placed parallel to the bile duct.

5-fold, but only 16-fold in Cyp7a1-tg mice In fatty acid synthe

5-fold, but only 1.6-fold in Cyp7a1-tg mice. In fatty acid synthesis pathway, a FXR target gene fatty acid synthase (FAS) was strongly induced, but the rate-limiting enzyme acetyl-CoA carboxylase (ACC) was induced only 90% in Cyp7a1-tg mice versus WT mice. However, microarray analysis did not indicate differential expression of any fatty acid synthesis genes, and IPA did not identify fatty acid metabolism as a top regulated pathway. Interestingly, mRNA levels of CD36, a major hepatic fatty Panobinostat acid transporter, were reduced in Cyp7a1-tg. Peroxisome proliferator-activated

receptor gamma (PPARγ), involved in the induction of hepatic fatty acid synthesis, was markedly reduced in both chow- and WD-fed Cyp7a1-tg mice. Liver pyruvate kinase (L-PK) and carbohydrate

response element-binding protein (ChREBP), involved in lipogenesis, were increased in chow-fed, but this website decreased in WD-fed, Cyp7a1-tg mice, compared to respective WT mice. These data suggest that reduced free fatty transport to hepatocytes and fatty acid synthesis in hepatocytes may prevent hepatic steatosis in Cyp7a1-tg mice. Given that induction of hepatic bile acid synthesis in Cyp7a1-tg mice is associated with increased expression of cholesterologenic and lipogenic genes, we injected 14C-labeled sodium acetate to chow-fed WT and Cyp7a1-tg mice to study hepatic fatty acid and cholesterol synthesis rate. As estimated by pmole of 14C-acetate incorporated into fatty acids and sterols, Fig.

1A shows that acetyl-CoA was mainly used for fatty acid synthesis in WT liver. Interestingly, cholesterol synthesis rate was increased ∼12-fold, whereas fatty acid synthesis rate was decreased ∼60% in Cyp7a1-tg mice, resulting in approximately equal incorporation of 14C-acetate into cholesterol and fatty acids. During the postprandial state, acetyl-CoA derived from glycolysis is used for both lipogenesis and cholesterologenesis. Induction acetylcholine of cholesterol synthesis provides cholesterol substrate to stimulate CYP7A1 activity and bile acid synthesis and, subsequently, stimulates fecal excretion of cholesterol and bile acids. To test the potential contribution of this route to hepatic lipid metabolism, we administered 14C-glucose to mice and measured 14C radioactivity in fecal neutral and acidic sterols. Figure 1B shows that fecal 14C radioactivity in neutral, acidic, and total sterols was markedly and rapidly increased in day 1 in Cyp7a1-tg mice, compared to WT mice. Fecal samples from Cyp7a1-tg mice contained significantly higher 14C radioactivity, accounting for ∼15% of 14C-glucose administered, compared to WT mice feces, which contained only ∼2% of 14C-glucose administered. In addition, the majority of fecal 14C radioactivity was recovered as neutral sterols. Fecal acidic sterols (bile acids) were increased 2-fold in Cyp7a1-tg mice.

5-fold, but only 16-fold in Cyp7a1-tg mice In fatty acid synthe

5-fold, but only 1.6-fold in Cyp7a1-tg mice. In fatty acid synthesis pathway, a FXR target gene fatty acid synthase (FAS) was strongly induced, but the rate-limiting enzyme acetyl-CoA carboxylase (ACC) was induced only 90% in Cyp7a1-tg mice versus WT mice. However, microarray analysis did not indicate differential expression of any fatty acid synthesis genes, and IPA did not identify fatty acid metabolism as a top regulated pathway. Interestingly, mRNA levels of CD36, a major hepatic fatty LDE225 order acid transporter, were reduced in Cyp7a1-tg. Peroxisome proliferator-activated

receptor gamma (PPARγ), involved in the induction of hepatic fatty acid synthesis, was markedly reduced in both chow- and WD-fed Cyp7a1-tg mice. Liver pyruvate kinase (L-PK) and carbohydrate

response element-binding protein (ChREBP), involved in lipogenesis, were increased in chow-fed, but find more decreased in WD-fed, Cyp7a1-tg mice, compared to respective WT mice. These data suggest that reduced free fatty transport to hepatocytes and fatty acid synthesis in hepatocytes may prevent hepatic steatosis in Cyp7a1-tg mice. Given that induction of hepatic bile acid synthesis in Cyp7a1-tg mice is associated with increased expression of cholesterologenic and lipogenic genes, we injected 14C-labeled sodium acetate to chow-fed WT and Cyp7a1-tg mice to study hepatic fatty acid and cholesterol synthesis rate. As estimated by pmole of 14C-acetate incorporated into fatty acids and sterols, Fig.

1A shows that acetyl-CoA was mainly used for fatty acid synthesis in WT liver. Interestingly, cholesterol synthesis rate was increased ∼12-fold, whereas fatty acid synthesis rate was decreased ∼60% in Cyp7a1-tg mice, resulting in approximately equal incorporation of 14C-acetate into cholesterol and fatty acids. During the postprandial state, acetyl-CoA derived from glycolysis is used for both lipogenesis and cholesterologenesis. Induction Clomifene of cholesterol synthesis provides cholesterol substrate to stimulate CYP7A1 activity and bile acid synthesis and, subsequently, stimulates fecal excretion of cholesterol and bile acids. To test the potential contribution of this route to hepatic lipid metabolism, we administered 14C-glucose to mice and measured 14C radioactivity in fecal neutral and acidic sterols. Figure 1B shows that fecal 14C radioactivity in neutral, acidic, and total sterols was markedly and rapidly increased in day 1 in Cyp7a1-tg mice, compared to WT mice. Fecal samples from Cyp7a1-tg mice contained significantly higher 14C radioactivity, accounting for ∼15% of 14C-glucose administered, compared to WT mice feces, which contained only ∼2% of 14C-glucose administered. In addition, the majority of fecal 14C radioactivity was recovered as neutral sterols. Fecal acidic sterols (bile acids) were increased 2-fold in Cyp7a1-tg mice.

Fresh frozen plasma and cryoprecipitates were traditionally the p

Fresh frozen plasma and cryoprecipitates were traditionally the principal treatments for patients with inherited clotting factor deficiencies. The revolutionary development of plasma-derived clotting factor concentrates (pdCFCs), via the fractionation of plasma [66], provided benefits for both haemophilia treaters and patients and enabled the widespread adoption of home treatment [67]. Large blood donor pools of up to 30 000 donations were used as a source of plasma to manufacture pdCFCs

and at the time there were no virucidal procedures or specific tests for infectious agents [68]. This led to an epidemic in the 1970s and early 1980s, with large numbers NVP-AUY922 of people with bleeding disorders becoming infected with blood-borne viruses such as hepatitis C virus (HCV) and HIV ERK inhibitor [66]. High infection rates were seen among haemophilia patients, particularly in those with severe haemophilia. Approximately 60% of patients were reported to have been infected with HIV [69] and almost 100% of patients treated with CFCs derived from pooled blood products developed non-A non-B hepatitis (today known as hepatitis C) [70]. Some countries with a national plasma supply had better

control of plasma and donors, and therefore were able to limit these epidemics. During this time, patients were also exposed to hepatitis B virus (HBV) infection, although symptomatic infection remains uncommon in haemophilia patients [71]. The high rates of infection observed within the haemophilia population had a significant impact on mortality rates. In the UK, prior to 1984, annual mortality for patients with haemophilia was Thymidine kinase 0.9% for severe disease and 0.4% for mild/moderate haemophilia. Post-1984 this remained relatively constant for patients without HIV, but increased progressively in patients infected with HIV to a maximum

of 12.7% for severe patients in 1994 and 13.1% for mild/moderate patients in 1996 (Fig. 4). The decrease in annual mortality rates after this period was due in part to the introduction of highly active antiretroviral therapy [72], and also to the introduction of screening procedures for HIV infection, starting from 1986. HCV complications also affected mortality rates. For example, in a UK cohort study, the mortality rates due to liver disease and liver cancer were found to be 16.7-times and 5.6-times higher, respectively, for haemophilia patients than in the general population [73]. Overall, the infection of haemophilia patients with HIV and HCV has placed severe health, economic and emotional burdens on affected patients and families, as well as on the wider bleeding disorders community [74]. The viral epidemic associated with pdCFCs acted as a trigger within the patient community and industry to drive the improvement of the processes involved in their manufacture.

Therefore, truncated Bid may preferentially activate Bak rather t

Therefore, truncated Bid may preferentially activate Bak rather than Bax in the liver. However, the present study also reveals that, in the absence of Bak, Bax plays an essential role in mediating the early onset of hepatocellular apoptosis. The most important finding of this study is that Bak/Bax deficiency failed to protect against the late onset of liver injury after Jo2 anti-Fas injection as well as Fas agonist injection. Wei et al.,32 in their historical paper establishing the importance of Bak and Bax in the mitochondrial pathway of apoptosis, reported

that hepatocytes were protected from Jo2-induced apoptosis in traditional Bak/Bax DKO mice (bak−/−bax−/−). Because perinatal lethality occurs with most CHIR-99021 nmr traditional Bak/Bax DKO mice, they could only analyze three animals, which did not enable detailed analysis of cell death due to Jo2 stimulation. The present study is the first to (1) thoroughly examine the impact of Bak and Bax in the liver using conditional KO mice and (2) demonstrate that Bak/Bax deficiency can protect against Fas-induced severe

injury in the early phase but not in the late phase. The late onset of liver injury Z VAD FMK observed in Bak/Bax DKO appeared to be apoptosis based on biochemical and morphological observations, including caspase activation, oligonucleosomal DNA breaks and, most importantly, identification of cell death with caspase dependency. In Tangeritin addition, the well-established necrotic pathway mediated by RIP kinase and/or CypD was not involved. However, the difference from apoptosis observed in Bak KO mice was the absence of mitochondrial alteration or cytochrome c–dependent caspase-9 processing in Bak/Bax DKO mice. We also confirmed that Bak/Bax-deficient mitochondria were not capable of releasing cytochrome c in the presence of truncated Bid (Supporting Fig. 5). These data support the idea that activation of the mitochondrial pathway of apoptosis is fully dependent on either Bak or Bax even in the late phase,

indicating at the same time that late onset of apoptosis takes place through an extrinsic pathway rather than the mitochondrial pathway. Although hepatocytes are generally considered to be type II cells, recent work has shown that the requirement of the mitochondrial pathway may be overcome through changes induced by in vitro culture conditions33, 34 or the strength of Fas stimulation.23 Schüngel et al.23 demonstrated that hepatocytes act as type II cells with a low-dose Jo2 injection (0.5 mg/kg) and act as type I cells with an extremely high-dose Jo2 injection (5 mg/kg). This agrees with the generally accepted idea that type I cells exhibit strong activation of DISC and caspase-8, which itself is sufficient to induce apoptosis, whereas type II cells exhibit weak activation and therefore require amplification of the apoptosis signal through the mitochondrial loop. In the present study, we used 1.5 mg/kg or 0.

Importantly, we implicate a putative role for the hepatic innate

Importantly, we implicate a putative role for the hepatic innate immune

system. The experimental design allowed us to investigate the relative influence of maternal obesity versus a postnatal obesogenic environment on progression of the NAFLD phenotype. The postweaning Chk inhibitor obesogenic diet had the greater influence on adiposity, hepatosteatosis, and markers of liver injury and fibrosis; however, there was an independent effect of maternal diet and a significant interaction between maternal and postweaning environments, which led to the most profound degree of liver injury observed. Moreover, we also observed that this disorder progressed with age. At 3 months, there was evidence of offspring obesity, adiposity, hepatosteatosis, and up-regulation of IL-6, TNF-α, and α-SMA as biochemical

markers of liver injury and fibrosis. By 12 months, there was more-profound evidence of hepatosteatosis, as assessed by the biochemical Selleckchem FDA-approved Drug Library markers and histological evidence of liver injury and fibrosis. We previously reported that offspring of obese mouse dams, when weaned onto standard chow, despite displaying hypertensive and dysmetabolic characteristics, did not exhibit a robust fatty liver phenotype.3 Here, we report similar hepatic tissue TG content Meloxicam in OffOb-SC, compared to controls, corroborated by histological steatosis assessment. Our findings parallel the findings of Bruce et al.,5 who reported hepatosteatosis in offspring exposed to maternal high-fat diet and weaned onto high-fat chow. OffOb-OD display

an accelerated and exaggerated liver phenotype, compared to offspring exposed only to a postweaning obesogenic diet. Therefore, taken together, the evidence suggests that developmental programming by diet-induced maternal obesity sensitizes the liver to the deleterious consequences of a second postnatal dietary challenge. Whereas Bruce et al. implicated phenotypic propagation of the liver phenotype by hepatic mitochondrial dysfunction and lipogenesis gene priming, we now suggest that maternal diet-induced obesity may also program offspring susceptibility to NAFLD by perturbation of the innate immune system. Offspring of obese dams reared on a hypercalorific diet, despite demonstrating increased KC numbers, showed impaired KC phagocytic activity and increased KC ROS production, which also revealed an apparent interaction between the maternal and postnatal environments. The current paradigm for the pathogenesis of NAFLD holds fat accumulation as a prerequisite for disease development.

Importantly, we implicate a putative role for the hepatic innate

Importantly, we implicate a putative role for the hepatic innate immune

system. The experimental design allowed us to investigate the relative influence of maternal obesity versus a postnatal obesogenic environment on progression of the NAFLD phenotype. The postweaning http://www.selleckchem.com/products/Adriamycin.html obesogenic diet had the greater influence on adiposity, hepatosteatosis, and markers of liver injury and fibrosis; however, there was an independent effect of maternal diet and a significant interaction between maternal and postweaning environments, which led to the most profound degree of liver injury observed. Moreover, we also observed that this disorder progressed with age. At 3 months, there was evidence of offspring obesity, adiposity, hepatosteatosis, and up-regulation of IL-6, TNF-α, and α-SMA as biochemical

markers of liver injury and fibrosis. By 12 months, there was more-profound evidence of hepatosteatosis, as assessed by the biochemical Stem Cells inhibitor markers and histological evidence of liver injury and fibrosis. We previously reported that offspring of obese mouse dams, when weaned onto standard chow, despite displaying hypertensive and dysmetabolic characteristics, did not exhibit a robust fatty liver phenotype.3 Here, we report similar hepatic tissue TG content Nintedanib (BIBF 1120) in OffOb-SC, compared to controls, corroborated by histological steatosis assessment. Our findings parallel the findings of Bruce et al.,5 who reported hepatosteatosis in offspring exposed to maternal high-fat diet and weaned onto high-fat chow. OffOb-OD display

an accelerated and exaggerated liver phenotype, compared to offspring exposed only to a postweaning obesogenic diet. Therefore, taken together, the evidence suggests that developmental programming by diet-induced maternal obesity sensitizes the liver to the deleterious consequences of a second postnatal dietary challenge. Whereas Bruce et al. implicated phenotypic propagation of the liver phenotype by hepatic mitochondrial dysfunction and lipogenesis gene priming, we now suggest that maternal diet-induced obesity may also program offspring susceptibility to NAFLD by perturbation of the innate immune system. Offspring of obese dams reared on a hypercalorific diet, despite demonstrating increased KC numbers, showed impaired KC phagocytic activity and increased KC ROS production, which also revealed an apparent interaction between the maternal and postnatal environments. The current paradigm for the pathogenesis of NAFLD holds fat accumulation as a prerequisite for disease development.

Importantly, we implicate a putative role for the hepatic innate

Importantly, we implicate a putative role for the hepatic innate immune

system. The experimental design allowed us to investigate the relative influence of maternal obesity versus a postnatal obesogenic environment on progression of the NAFLD phenotype. The postweaning learn more obesogenic diet had the greater influence on adiposity, hepatosteatosis, and markers of liver injury and fibrosis; however, there was an independent effect of maternal diet and a significant interaction between maternal and postweaning environments, which led to the most profound degree of liver injury observed. Moreover, we also observed that this disorder progressed with age. At 3 months, there was evidence of offspring obesity, adiposity, hepatosteatosis, and up-regulation of IL-6, TNF-α, and α-SMA as biochemical

markers of liver injury and fibrosis. By 12 months, there was more-profound evidence of hepatosteatosis, as assessed by the biochemical Sorafenib molecular weight markers and histological evidence of liver injury and fibrosis. We previously reported that offspring of obese mouse dams, when weaned onto standard chow, despite displaying hypertensive and dysmetabolic characteristics, did not exhibit a robust fatty liver phenotype.3 Here, we report similar hepatic tissue TG content Buspirone HCl in OffOb-SC, compared to controls, corroborated by histological steatosis assessment. Our findings parallel the findings of Bruce et al.,5 who reported hepatosteatosis in offspring exposed to maternal high-fat diet and weaned onto high-fat chow. OffOb-OD display

an accelerated and exaggerated liver phenotype, compared to offspring exposed only to a postweaning obesogenic diet. Therefore, taken together, the evidence suggests that developmental programming by diet-induced maternal obesity sensitizes the liver to the deleterious consequences of a second postnatal dietary challenge. Whereas Bruce et al. implicated phenotypic propagation of the liver phenotype by hepatic mitochondrial dysfunction and lipogenesis gene priming, we now suggest that maternal diet-induced obesity may also program offspring susceptibility to NAFLD by perturbation of the innate immune system. Offspring of obese dams reared on a hypercalorific diet, despite demonstrating increased KC numbers, showed impaired KC phagocytic activity and increased KC ROS production, which also revealed an apparent interaction between the maternal and postnatal environments. The current paradigm for the pathogenesis of NAFLD holds fat accumulation as a prerequisite for disease development.