Progression Of Hepatic Steatosis Research Articles

Obstructive Sleep Apnea and Non-Alcoholic Fatty Liver Disease: Is the Liver Another Target?

Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.

Non‐alcoholic steatohepatitis‐induced fibrosis: Toll‐like receptors, reactive oxygen species and Jun N‐terminal kinase

Non-alcoholic steatohepatitis (NASH) represents the progression of hepatic steatosis to streatohepatitis, fibrosis and cirrhosis. Three signaling pathways have been associated with this progression; Toll-like receptors, reactive oxygen species and Jun N-terminal kinase. This review will describe how activation of these three pathways is required for development of fibrosis in murine models of NASH. The three pathways are related and synergistic through intracellular cross-talk. Disruption of any of these pathways may inhibit NASH-induced fibrosis and are potential targets for therapeutic intervention.

New genes involved in hepatic steatosis

To summarize currently available information about the mechanisms involved in liver fat accumulation. The contribution of functional genomics approaches, such as those represented by high-throughput analysis and genetically modified mice, may envision a complex network involving fatty acid, triglyceride and phospholipid metabolisms and lipid droplet dynamics. Likewise, it may pose an exquisite regulation exerted through insulin, glucocorticoids, thyroid hormones, transcription factors and microRNAs, orchestrated with sexual differences and able to respond to environmental factors such as nutritional or viral influences among others. The information gathered will facilitate further research to complete gaps of interacting pieces among regulators and new contributing agents emerging from high-throughput analyses. With this new paradigm, new biomarkers able to discriminate the progression of hepatic steatosis into human steatohepatitis will eventually emerge, and hopefully new therapeutic approaches will be developed.

The Hepatic Inflammsome Has an Increased NK-T and CD8+ T- Cell Signature in a Murine Model of Fibrotic Nonalcoholic Steatohepatitis (NASH)

High fat diet induced models of simple hepatic steatosis have been shown to result in a decreased hepatic natural killerT (NKT) cell population. Interestingly, NKT cells are known to correlate positively with the development of adipose tissue inflammation and glucose intolerance in diet-induced obesity. Recent data implicates refined carbohydrates (Fructose) in the progression of hepatic steatosis to advanced fibrotic NASH in humans. This has also been replicated in a novel model of obesity and NASH with fibrosis in mice. We therefore hypothesized that NKT cells populate the livers in a murine model of advanced NASH with fibrosis. Methods: Adult male C57BL6 mice were randomly assigned to control (C) or high fat high carbohydrate diet (HFHC). The C group received regular chow and water while the HFHC group received diet with Medium Chain Triglycerides (MCT; 58% kcal) and water supplemented with 55% fructose & 45% sucrose. Mice were sacrificed at 16 wks of age and underwent hepatic mononuclear cell phenotyping by flow cytometry. Results: Mice receiving HFHC diet gained significantly more weight than C fed mice starting at 4 wk (p<0.01), with a Mean ± SE weight of 45.84±1.4g at 16 wk compared to 31.33±1.0g for C fed mice (p<0.0001). Fasting glucose was higher in HFHC mice at 16 wks (176.3±9.2 mg/dl; p=0.001). Liver weight at 16 weeks was higher in the HFHC group (2.44±0.2g) compared to the C fed mice (1.47±0.03g; p<0.01). Steatosis as measured by liver triacylglycerol (TG) content was also higher in HFHC mice at 16 wks (2354±487.8 mg/dl/100 mg wet liver) compared to the C fed mice (p= 0.001). Inflammation as measured by serum alanine aminotransferase (ALT) levels was higher in HFHC mice (135.8±24.28 IU/L) at 16 wks compared to the C fed mice (p=0.019). Flow cytometric analysis identified increased NK-T cell (CD3+NK1.1+) signature in mice receiving HFHC (3.7±2.3x104 cells) compared to C fed mice (1.1±0.6x104 cells; p=0.02). While hepatic CD1d-restricted invariant NK-T CD4+ and CD8+ cell populations remained unchanged, total CD3+CD8+ T-cells significantly increased in the HFHC group (1.93±0.79x105) vs. C fed (1.0±0.7x105; p=0.04). A corresponding increase in CD8+ T-cells expressing the activation marker CD69 was also seen [(2.02±1.01x104 (C) vs 6.85±2.6x104 (HFHC); p<0.01]. Liver fibrosis was visible at sacrifice in majority of the HFHC fed mice (Stage 1c and 2) while none was seen in C diet fed mice. Conclusion: HFHC diet produces a relatively rapid and progressive liver injury resulting in NASH with fibrosis in a background of diet-induced obesity. In this system, which closely resembles the human phenotype of advanced NASH with fibrosis, we observed a significant increase in hepatic NK-T and CD8+ T-cells. These cell types may potentially typify the hepatic inflammasome in the progression of human disease to NASH with fibrosis.

Disruption of the 12/15-lipoxygenase gene (Alox15) protects hyperlipidemic mice from nonalcoholic fatty liver disease

We have shown that Alox15, the gene encoding for 12/15-lipoxygenase (12/15-LO), is markedly up-regulated in livers from apolipoprotein E-deficient (ApoE(-/-)) mice, which spontaneously develop nonalcoholic fatty liver disease secondary to hyperlipidemia. In the current study, we used ApoE(-/-) mice with a targeted disruption of the Alox15 gene to assess the role of 12/15-LO in the development and progression of hepatic steatosis and inflammation. Compared with ApoE(-/-) mice, which exhibited extensive hepatic lipid accumulation and exacerbated inflammatory injury, ApoE/12/15-LO double-knockout (ApoE(-/-)/12/15-LO(-/-)) mice showed reduced serum alanine aminotransferase levels; decreased hepatic steatosis, inflammation, and macrophage infiltration; and decreased fatty acid synthase, tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-18, and IL-6 expression. Remarkably, disruption of Alox15 attenuated glucose intolerance and high-fat diet-induced insulin resistance, up-regulated insulin receptor substrate-2, and exerted opposite effects on hepatic c-Jun amino-terminal kinase and adenosine monophosphate-activated protein kinase phosphorylation, known negative and positive regulators of insulin signaling, respectively. In adipose tissue, the absence of Alox15 induced significant reductions in the expression of the proinflammatory and insulin-resistant adipokines MCP-1, TNFα, and resistin while increasing the expression of glucose transporter-4. Interestingly, compared with ApoE(-/-) mice, which exhibited increased hepatic caspase-3 staining, ApoE(-/-)/12/15-LO(-/-) mice showed attenuated hepatocellular injury. Consistent with this finding, hepatocytes isolated from ApoE(-/-) mice were more vulnerable to TNFα-induced programmed cell death, an effect that was not observed in hepatocytes carrying a targeted disruption of the Alox15 gene. Collectively, our data suggest a potentially relevant mechanism linking 12/15-LO to the promotion of hepatic steatosis, insulin resistance, and inflammation in experimental liver disease of metabolic origin.

Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice

Inflammatory processes have an important role in the development of hepatic steatosis and progression to nonalcoholic steatohepatitis (NASH). Interleukin-6 (IL-6) is known to be a proinflammatory cytokine, but also promotes liver regeneration and protects the liver against various forms of damage. The role of IL-6/Glycoprotein130 (GP130) in NASH remains unclear. In this study, we determined whether blocking IL-6/GP130 signaling prevents progression of steatohepatitis in a mouse NASH model. Six-week-old male C57/BL6 mice were fed either chow control or a methionine choline-deficient (MCD) diet for 8 weeks. Half of the MCD diet-fed mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor antibody (MR16-1), intraperitoneally twice weekly, the remainder and chow-fed mice were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, apoptosis, markers of lipid peroxidation/oxidant stress and IL-6-related gene expressions were evaluated. MR16-1 treatment decreased signal transducer and activator of transcription 3 activities and expression of suppressor of cytokine signaling 3 in MCD diet-treated mouse livers. Although this treatment enhanced intrahepatic lipid accumulation accompanied by increased sterol regulatory element-binding protein 1 and decreased peroxisome proliferator-activated receptor-α expression, elevated plasma alanine aminotransferase levels were improved with decreased plasma free fatty acid levels, lipid peroxidation/oxidant stress and hepatic apoptosis. Blocking IL-6/GP130 signaling by MR16-1 enhanced MCD diet-induced hepatic steatosis, but ameliorated liver injury. These findings suggest that hepatic IL-6 signaling has a protective role against the progression of hepatic steatosis but may enhance liver inflammation.

Cide-a and Cide-c are induced in the progression of hepatic steatosis and inhibited by eicosapentaenoic acid

Cide-a and Cide-c belong to the cell death-inducing DNA fragmentation factor-α-like effector family. Recent evidences suggest that these proteins may be involved in lipid accumulation in liver and adipose tissues. We confirmed that in the high-fat/high-sucrose diet-induced murine model of hepatic steatosis, the expression levels of the Cide-a and Cide-c genes were markedly and time-dependently increased, but returned to normal levels following improvement of hepatic steatosis by eicosapentaenoic acid (EPA) administration. Levels of expression of the Cide-a and Cide-c genes correlated well with plasma ALT. EPA inhibited the promoter activity of the Cide-a gene in vitro. Sterol regulatory element-binding protein-1 (SREBP-1) markedly enhanced the promoter activity of Cide-a, and EPA inhibited the expression of Cide-a mRNA. SREBP-1 and EPA did not affect those of Cide-c. These findings indicate that Cide-a and Cide-c are closely involved in the progression of hepatic steatosis, and that EPA inhibits Cide-a gene expression through SREBP-1 regulation.

Effect of Pancreaticoduodenectomy on the Course of Hepatic Steatosis

The progression of hepatic steatosis after pancreaticoduodenectomy (PD) is controversial. This study was designed to determine whether PD would influence the course of hepatic steatosis. Patients admitted for PD and distal pancreatectomy (DP) from January 2004 to January 2008 were enrolled. Exclusion criteria included liver metastasis, severe obesity (body mass index >30), diabetic mellitus, excessive alcohol consumption, and unavailable preoperative and 6-month postoperative unenhanced CT images. The pre-PD and post-PD liver attenuation, ratio, and difference of liver-to-spleen attenuation between liver and spleen attenuation were compared. Fifty patients who underwent PD and 20 patients who underwent DP were eligible. The mean follow-up period was 18.2 +/- 1.6 months for the PD group and 19.7 +/- 1.7 months for the DP group. Liver attenuation after PD was significantly decreased from 52.3 +/- 1.1 H. to 47.6 +/- 2 H. (p = 0.044), but no difference was observed in spleen attenuation. The liver-to-spleen attenuation ratio after PD also was significantly decreased: 1.12 +/- 0.02 versus 1.01 +/- 0.04 (p = 0.033). No difference in liver attenuation was found in the DP group. The female gender was a significant risk factor. The liver attenuation of CT images decreases in patients who receive PD, which implicates that hepatic steatosis can develop after PD; however, the mechanism needs to be elucidated.

The prostacyclin analog beraprost sodium ameliorates characteristics of metabolic syndrome in obese Zucker (fatty) rats.

OBJECTIVEThe prostacyclin analog, beraprost sodium (BPS), was examined for its potential to improve the symptoms of obesity-type diabetes (i.e., hyperglycemia, hyperinsulinemia, dyslipidemia, histopathologic changes, and diabetic complications).RESEARCH DESIGN AND METHODSObese Zucker rats, an experimental model of genetic obesity-induced type 2 diabetes, were repeatedly administered BPS at oral doses of 0.2 or 0.6 mg · kg−1 · day−1 b.i.d. for 12 weeks, and serum chemistry, urinalysis, and histopathologic examination were performed.RESULTSBPS dose-dependently suppressed serum glucose, insulin, triglyceride, and cholesterol levels in obese animals. In oral glucose tolerance test, BPS suppressed the post–glucose-loading elevation of serum glucose in a dose-dependent manner. Urinary N-acetyl-β-D-glucosaminidase was significantly lower in BPS-treated obese animals compared with control animals, although no significant differences were observed in urinary protein levels between the BPS-treated groups and the control group. In addition, histopathologic examination revealed significant protective effects of BPS against renal disorder in obese animals. Histopathologically, BPS also inhibited the progression of hepatic steatosis, hypertrophy of adipose tissue, and pancreatic fibrosis. Furthermore, thermographic analysis of the hind limb sole skin surface indicated a significant increase in temperature in BPS-treated animals, compared with control animals, which was likely due to improved blood circulation by administration of BPS.CONCLUSIONSBPS suppressed the pathogenesis and development of diabetes and its complication, nephropathy, which was presumably accompanied by improving glucose intolerance and insulin resistance in obese Zucker rats.

Nutritional related liver disease: targeting the endoplasmic reticulum stress

Nutritional hepatic disorders are spreading worldwide associated to obesity and type 2 diabetes. The underlying mechanisms leading to the development of hepatic steatosis and its complications are not fully understood. The endoplasmic reticulum (ER) stress response has recently been proposed to play a crucial role in the setting of these pathologies. This review will evaluate the late discoveries highlighting ER stress as a major actor in the development of nutritional liver diseases. Activation of ER stress has been reported in the fatty liver of obese rodents and obese individuals. The mechanisms by which ER stress leads to the development of hepatic steatosis have been recently documented. ER stress has been shown to directly activate the lipogenic transcription factor SREBP-1c (sterol regulatory element binding protein-1c) conducting to an induction of the lipogenic pathway. ER stress activation is also associated with impaired VLDL (very low density lipoprotein) secretion. ER stress could also have a role in hepatic steatosis progression by triggering inflammation and fibrosis. In rodents, therapies aiming to reduce ER stress have fully demonstrated their efficiency in the treatment of hepatic steatosis. ER stress has been recently involved in the development of hepatic steatosis. Thus, ER stress could represent in the future an eligible therapeutic target for the treatment of nonalcoholic fatty liver disease. However, as ER stress is a fundamental mechanism involved in cell survival, any modification of this pathway must be carefully assessed.

W1526 Effect of Pancreaticoduodenectomy On the Course of Hepatic Steatosis

Background The progression of hepatic steatosis after pancreaticoduodenectomy (PD) is controversial. This study was designed to determine whether PD would influence the course of hepatic steatosis.

Highly purified eicosapentaenoic acid prevents the progression of hepatic steatosis by repressing monounsaturated fatty acid synthesis in high-fat/high-sucrose diet-fed mice

Eicosapentaenoic acid (EPA) is a member of the family of n-3 polyunsaturated fatty acids (PUFAs) that are clinically used to treat hypertriglyceridemia. The triglyceride (TG) lowering effect is likely due to an alteration in lipid metabolism in the liver, but details have not been fully elucidated. To assess the effects of EPA on hepatic TG metabolism, mice were fed a high-fat and high-sucrose diet (HFHSD) for 2 weeks and were given highly purified EPA ethyl ester (EPA-E) daily by gavage. The HFHSD diet increased the hepatic TG content and the composition of monounsaturated fatty acids (MUFAs). EPA significantly suppressed the hepatic TG content that was increased by the HFHSD diet. EPA also altered the composition of fatty acids by lowering the MUFAs C16:1 and C18:1 and increasing n-3 PUFAs, including EPA and docosahexaenoic acid (DHA). Linear regression analysis revealed that hepatic TG content was significantly correlated with the ratios of C16:1/C16:0, C18:1/C18:0, and MUFA/n-3 PUFA, but was not correlated with the n-6/n-3 PUFA ratio. EPA also decreased the hepatic mRNA expression and nuclear protein level of sterol regulatory element binding protein-1c (SREBP-1c). This was reflected in the levels of lipogenic genes, such as acetyl-CoA carboxylase α (ACCα), fatty acid synthase, stearoyl-CoA desaturase 1 (SCD1), and glycerol-3-phosphate acyltransferase (GPAT), which are regulated by SREBP-1c. In conclusion, oral administration of EPA-E ameliorates hepatic fat accumulation by suppressing TG synthesis enzymes regulated by SREBP-1 and decreases hepatic MUFAs accumulation by SCD1.

Regulatory effects of arachidonate 5-lipoxygenase on hepatic microsomal TG transfer protein activity and VLDL-triglyceride and apoB secretion in obese mice

As 5-lipoxygenase (5-LO) is an emerging target in obesity and insulin resistance, we have investigated whether this arachidonate pathway is also implicated in the progression of obesity-related fatty liver disease. Our results show that 5-LO activity and 5-LO-derived product levels are significantly elevated in the liver of obese ob/ob mice with respect to wild-type controls. Treatment of ob/ob mice with a selective 5-LO inhibitor exerted a remarkable protection from hepatic steatosis as revealed by decreased oil red-O staining and reduced hepatic triglyceride (TG) concentrations. In addition, 5-LO inhibition in ob/ob mice downregulated genes involved in hepatic fatty acid uptake (i.e., L-FABP and FAT/CD36) and normalized peroxisome proliferator-activated receptor alpha (PPARalpha) and acyl-CoA oxidase expression, whereas the expression of lipogenic genes [i.e., fatty acid synthase (FASN) and SREBP-1c] remained unaltered. Furthermore, 5-LO inhibition restored hepatic microsomal TG transfer protein (MTP) activity in parallel with a stimulation of hepatic VLDL-TG and apoB secretion in ob/ob mice. Consistent with these findings, 5-LO products directly inhibited MTP activity and triggered cytosolic TG accumulation in CC-1 cells, a murine hepatocyte cell line. Taken together, these findings identify a novel steatogenic role for 5-LO in the liver through mechanisms involving the regulation of hepatic MTP activity and VLDL-TG and apoB secretion.

Fructose and carbonyl metabolites as endogenous toxins

Dietary fructose consumption is one of the environmental factors contributing to the development of obesity and a fatty liver (hepatic steatosis). A two-hit hypothesis has been proposed for progression of hepatic steatosis to the more serious non-alcoholic steatosis (NASH), with the first hit being hepatic steatosis, and the second hit being inflammation and associated oxidative stress caused by reactive oxygen species (ROS) formation. As well, fructose-fed rats develop insulin resistance and serum levels of methylglyoxal, a glycolytic metabolite, are increased. Previously we reported that glyoxal-induced hepatocyte cytotoxicity could be attributed to mitochondrial toxicity as mitochondrial membrane potential was decreased and cytotoxicity was increased several orders of magnitude by low non-cytotoxic doses of H 2O 2 (hepatocyte inflammation model). In this study, we have assessed the toxicity of fructose towards hepatocytes and investigated the molecular cytotoxic mechanisms involved. Fructose itself was only toxic at 1.5 M, whereas 12 mM caused 50% cell death in 2 h if the hepatocytes were exposed to a non-cytotoxic dose of H 2O 2 continuously generated by glucose and glucose oxidase. The cytotoxic mechanism involved oxidative stress as ROS and H 2O 2 formation preceded cytotoxicity, and cytotoxicity was prevented by radical scavengers, lipid antioxidants and ROS scavengers. It is proposed that the highly potent Fenton derived ROS catalyse the oxidation of fructose and particularly its carbonyl metabolites glycolaldehyde, dihydroxyacetone, glyceraldehyde. The carbon radicals and glyoxal formed compromise the cell's resistance to H 2O 2.

Correlation of serum adiponectin levels and hepatic steatosis in hepatitis c virus genotype 1 infection

Steatosis is an important cofactor in hepatitis C virus (HCV) because it is associated with fibrosis and reduces early and sustained virologic response. Recent studies suggest that HCV genotype 1 is not steatogenic if additional risk factors are not present. Because hypoadiponectinemia was found to be a feature of nonalcoholic steatohepatitis (NASH) independent of insulin resistance, its level in patients with hepatitis C genotype can reveal the optimal therapeutic strategy. This study was conducted to determine the role of the relationship between steatosis and serum adiponectin levels in the progression of liver damage in HCV genotype 1 without known risk factors for NASH. Patients (n=50) with biopsy-proven chronic hepatitis C (CHC), positive HCV RNA, and raised alanine aminotransferase were enrolled. They were carefully selected to rule out possible confounding factors for the presence of steatosis and additional systemic or liver disease. Associations between serum adiponectin levels and grade of steatosis, histologic activity index (HAI), fibrosis grade of liver biopsies, patient age, HCV viral load, and serum transaminase activities were studied. Also, adiponectin levels were compared with those of a control group of 30 healthy volunteers with normal ultrasound findings of the upper abdomen who had no known NASH risk factors. The investigators found that adiponectin levels in patients with CHC genotype 1 were similar to those in healthy subjects. No significant association was found between adiponectin levels and severity of steatosis, HCV RNA levels, HAI, transaminases, and fibrosis. Steatosis was present in 41 patients (82%) with CHC. Multivariate analysis of data on 50 patients revealed that severity of steatosis was independently related to age alone (P=.03). A correlation between HCV RNA load and HAI was observed (P=.02; r=0.712). HAI also was associated with stage of fibrosis (P=.00; r= 0.612). In cases of chronic HCV genotype 1 hepatitis, steatosis is a common histologic feature, although no risk factors are known. Results presented here cannot establish an association between adiponectin and severity of steatosis when risk factors for steatosis are unknown. Additional studies are needed to discover a metabolic treatment that would seek to improve the progression of hepatic steatosis in CHC infection.

Apolipoprotein-AII Concentrations are Associated With Liver Steatosis in Patients With Chronic Hepatitis C

It has been shown that the hepatitis C virus (HCV) core protein reduces the activity of the microsomal triglyceride transfer protein (MTP) and could lead to steatosis in HCV-infected patients. Experimentally, apolipoprotein-AII (apoAII), which restores triglyceride secretion altered by the HCV core protein, could be protective against HCV steatosis. On the other hand, increasing plasma concentrations of mouse apoAII in transgenic mice produced several aspects of insulin-resistance syndrome, which also is implicated in the pathogenesis of HCV steatosis. This study was designed to investigate the role of apoAII in HCV-related steatosis in humans. Sixty-five hospitalized patients with chronic HCV were included in this study to assess the effects of apoAII, body mass index (BMI), age, insulin sensibility (HOMA), and leptin level on steatosis. Steatosis was observed in 55.3% of patients. Apo-AII was significantly associated with HOMA and with leptin concentrations. In univariate analyses, age, BMI, increased leptin level, increased HOMA, and increased apoAII concentration were associated with steatosis. In multivariate analysis, steatosis was associated with apoAII concentration, age, gender, and BMI. Contrary to previous hypotheses, apoAII is not a protective factor against HCV steatosis but is significantly associated with the development of liver steatosis. The fact that the plasma levels of apoAII correlate with HOMA and leptin levels in HCV-infected patients suggests that apoAII may contribute to hepatic steatosis progression in relationship to visceral obesity, insulin resistance, and metabolism of triglyceride-rich lipoproteins.

Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model

Adipose tissue produces a number of adipocytokines, including adiponectin, leptin, and tumor necrosis factor-alpha. Obesity, which is associated with low plasma adiponectin levels, is an independent risk factor for various liver diseases including nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the effects of adiponectin on the progression of NASH to cirrhosis and tumor formation using adiponectin-knockout (KO) mice. Using a choline-deficient L-amino acid-defined (CDAA) diet-induced mouse NASH model, liver histology and oxidative stress markers were investigated in KO and wild-type (WT) mice. Hepatic steatosis was enhanced to a greater extent in KO mice, compared to WT mice after a 1-week CDAA diet. After 24 weeks, 6 out of 14 KO mice developed liver cirrhosis and hepatic tumors, whereas the 15 WT mice showed only simple steatosis. In KO mice, hepatic cytochrome P450 2E1 levels were upregulated, and markers of oxidative stress (thiobarbituric acid reactive substances, 8-hydroxydeoxyguanosine-positive cells) were significantly increased compared with WT mice. Our results indicate that lack of adiponectin enhances the progression of hepatic steatosis, fibrosis, and hepatic tumor formation in an animal model of NASH. Hypoadiponectinemia in obesity could be a risk factor for NASH-related hepatic tumor formation.

Is the slippery slope from steatosis to steatohepatitis paved with triglyceride or cholesterol?

Accumulation of hepatic lipids has been thought to trigger the inflammation, apoptosis, and fibrosis that characterize progression of hepatic steatosis to steatohepatitis and cirrhosis. In this issue of Cell Metabolism, Marí et al. (2006) provide evidence for excessive mitochondrial free cholesterol as a cause of the progession of steatosis to more severe liver disease.

Future directions in reducing hepatic lipotoxicity

In recent years, the increase in dietary energy availability and sedentary lifestyles has increased the development of obesity. Adipose tissue plays an important role in preventing the accumulation of lipids in other nonadipose tissues. However, during obesity, adipocytes become dysfunctional and, as a consequence, the fatty acids (FA) from adipocytes are released mainly into the liver. In the liver, FA are esterified to form triacylglycerols (TG) and there is also an increase inde novo synthesis of FA due to the hyperinsulinemia present during obesity. As a result, an accumulation of TG in the liver occurs, resulting in hepatic steatosis. Lipotoxicity refers to the FA that exceed the capacity of nonadipose tissues to oxidize them, thus enhancing the metabolic flux of FA to form harmful products involved in the progression of hepatic steatosis to hepatic fibrosis and cirrhosis. As an integral strategy to prevent or treat the consequences of lipotoxicity in humans, healthcare professionals must consider ne...

Mechanisms of Disease: hepatic steatosis in type 2 diabetes—pathogenesis and clinical relevance

Hepatic steatosis is defined by an increased content of hepatocellular lipids (HCLs) and is frequently observed in insulin-resistant states including type 2 diabetes mellitus. A dietary excess of saturated fat contributes significantly to HCL accumulation. Elevated HCL levels mainly account for hepatic insulin resistance, which is probably mediated by partitioning of free fatty acids to the liver (fat overflow) and by an imbalance of adipocytokines (decreased adiponectin and/or increased proinflammatory cytokines). Both free fatty acids and adipocytokines activate inflammatory pathways that include protein kinase C, the transcription factor nuclear factor kappaB, and c-Jun N-terminal kinase 1 and can thereby accelerate the progression of hepatic steatosis to nonalcoholic steatohepatitis and cirrhosis. Proton magnetic resonance spectroscopy has made it possible to quantify HCL concentrations and to detect even small changes in these concentrations in clinical settings. Moderately hypocaloric, fat-reduced diets can decrease HCL levels by approximately 40-80% in parallel with loss of up to 8% of body weight. Treatment with thiazolidinediones (e.g. pioglitazone and rosiglitazone) reduces HCL levels by 30-50% by modulating insulin sensitivity and endocrine function of adipose tissue in type 2 diabetes. Metformin improves hepatic insulin action without affecting HCL levels, whereas insulin infusion for 67 h increases HCL levels by approximately 18%; furthermore, HCL levels positively correlate with the insulin dosage in insulin-treated type 2 diabetes. In conclusion, liver fat is a critical determinant of metabolic fluxes and inflammatory processes, thereby representing an important therapeutic target in insulin resistance and type 2 diabetes mellitus.