Fatty Liver Tissue Research Articles

Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice.

Inflammatory factors secreted by macrophages play an important role in obesity-related insulin resistance. Being at the crossroads of a nutrient-hormonal signalling network, the mammalian target of rapamycin complex 1 (mTORC1) controls important functions in the regulation of energy balance and peripheral metabolism. However, the role of macrophage mTORC1 in insulin resistance is still unclear. In the current study, we investigated the physiological role of macrophage mTORC1 in regulating inflammation and insulin sensitivity. We generated mice deficient in the regulatory associated protein of mTOR (Raptor) in macrophages, by crossing Raptor (also known as Rptor) floxed mice (Raptor (flox/flox)) with mice expressing Cre recombinase under the control of the Lysm-Cre promoter (Mac-Raptor (KO)). We fed mice chow or high-fat diet (HFD) and assessed insulin sensitivity in liver, muscle and adipose tissue. Subsequently, we measured inflammatory gene expression in liver and adipose tissue and investigated the role of Raptor deficiency in the regulation of inflammatory responses in peritoneal macrophages from HFD-fed mice or in palmitic acid-stimulated bone marrow-derived macrophages (BMDMs). Mac-Raptor (KO) mice fed HFD had improved systemic insulin sensitivity compared with Raptor (flox/flox) mice. Macrophage Raptor deficiency reduced inflammatory gene expression in liver and adipose tissue, fatty liver and adipose tissue macrophage content in response to HFD. In peritoneal macrophages from mice fed with an HFD for 12weeks, macrophage Raptor deficiency decreased inflammatory gene expression, through attenuation of the inactivation of Akt and subsequent inhibition of the inositol-requiring element 1α/clun NH2-terminal kinase-nuclear factor kappa-light-chain-enhancer of activated B cells (IRE1α/JNK/NFκB) pathways. Similarly, mTOR inhibition as a result of Raptor deficiency or rapamycin treatment decreased palmitic acid-induced inflammatory gene expression in BMDMs in vitro. The disruption of mTORC1 signalling in macrophages protects mice against inflammation and insulin resistance potentially by inhibiting HFD- and palmitic acid-induced IRE1α/JNK/NFκB pathway activation.

Raman imaging providing insights into chemical composition of lipid droplets of different size and origin: in hepatocytes and endothelium.

In this work, 3D linear Raman spectroscopy was used to study lipid droplets (LDs) ex vivo in liver tissue and also in vitro in a single endothelial cell. Spectroscopic measurements combined with fluorescence microscopy and/or histochemical staining gave complex chemical information about LD composition and enabled detailed investigations of the changes occurring in various pathological states. Lipid analysis in fatty liver tissue was performed using a dietary mouse model of liver steatosis, induced by a high fat diet (HFD). HFD is characterized by a high percentage of calories from saturated fat (60%) and reflects closely the detrimental effects of dietary habits responsible for increased morbidity due to obesity and its complications in well-developed Western societies. Such diets lead to obesity, hyperlipidemia, insulin resistance, and steatosis that may also be linked to endothelial dysfunction. In the present work, Raman spectroscopy was applied to characterized chemical composition of lipid droplets in hepatocytes from mice fed HFD and in the endothelium treated with exogenous unsaturated free fatty acid (arachidonic acid). The results demonstrate the usefulness of Raman spectroscopy to characterize intracellular lipid distribution in 2D and 3D images and can be used to determine the degree of saturation. Raman spectroscopy shows the potential to be a valuable tool for studying the role of LDs in physiology and pathology. The method is generally applicable for the determination of LDs of different size, origin, and composition. Moreover, for the first time, the process of LD formation in the endothelium was detected and visualized in 3D.

Effect of methanol extracts of three dietary plants growing in Egypt on mice fed with high fat diet

The objective of the present investigation was to evaluate the preventive effect of methanol extracts of three dietary plants growing in Egypt; Cassia fistula (Family Fabaceae), Cynara scolymus (Family Asteraceae) and Glycine max (Family fabaceae) on body weight gain, hepatic and kidney index, food intake, lipid profile and serum enzymes in mice fed high fat diet during different periods 4, 11 and 17 weeks. For this purpose, the mice were divided into groups of eight mice each group as follows; normal group, high fat diet (HFD) group , HFD + methanol extract of C. fistula group, HFD + Methanol extract of C. scolymus group and HFD + methanol extract of G. max group, the dose of plant extract in each treated group was 100 mg /Kg body weight. After 4 weeks to 17 weeks the body weight, the relative liver weight, lipid profile and serum enzymes increased in the control group (HFD) compared to the normal. Treatment with each plant plant extract led to reduction in body weight and improvement of lipid and serum enzymes of the treated mice compared to the control groups. Extract of G.max showed the highest activity. These results were supported by hepatic histology examination which showed improvement of fatty liver tissue.

Quantitative characterization of fatty liver disease using x-ray scattering

Nonalcoholic fatty liver disease (NAFLD) is a dynamic condition in which fat abnormally accumulates within the hepatocytes. It is believed to be a marker of risk of later chronic liver diseases, such as liver cirrhosis and carcinoma. The fat content in liver biopsies determines its validity for liver transplantation. Transplantation of livers with severe NAFLD is associated with a high risk of primary non-function. Moreover, NAFLD is recognized as a clinically important feature that influences patient morbidity and mortality after hepatic resection. Unfortunately, there is a lack in a precise, reliable and reproducible method for quantification of NAFLD. This work suggests a method for the quantification of NAFLD. The method is based on the fact that fatty liver tissue would have a characteristic x-ray scattering profile with a relatively intense fat peak at a momentum transfer value of 1.1nm−1 compared to a soft tissue peak at 1.6nm−1. The fat content in normal and fatty liver is plotted against three profile characterization parameters (ratio of peak intensities, ratio of area under peaks and ratio of area under fat peak to total profile area) for measured and Monte Carlo simulated x-ray scattering profiles. Results show a high linear dependence (R2>0.9) of the characterization parameters on the liver fat content with a reported high correlation coefficient (>0.9) between measured and simulated data. These results indicate that the current method probably offers reliable quantification of fatty liver disease.

Impact of dietary induced fatty liver on mitochondrial oxidative phosphorylation

High fat (HF) diet has been linked to mitochondrial dysfunction. Alteration of HF diet duration has shown that although mitochondrial impairments are present initially (2–4 weeks), these impairments are abolished or exceed control level function after prolonged HF feeding (>; 8 weeks). Male C‐57 mice (n=14) were randomly assigned to one of two dietary groups; chow (CH, 10% kcal fat) and high fat (HF, 60% kcal fat). HF mice were obese with elevated liver triglycerides. Isolated mitochondria from mouse liver tissue were measured using high‐resolution respirometry. Animals within the HF group possessed higher state 3 & 4 respiration (p<0.05), as well as higher respiratory control ratios (p<0.05). Mitochondria are termed to be in state 3 respiration when actively respiring, meaning the rate where they are capable of converting adenosine diphosphate (ADP) to adenosine triphosphate (ATP) through oxygen consumption. State 4 refers to the rate of oxygen depletion after all ADP has been phosphorylated, also termed leak respiration. This indicates that mitochondria in HF animals are able to adapt to metabolic stressors such as a high fat diet by elevating state 3 respiratory rates above normal levels. Moreover, mitochondria can increase their active respiratory rate within fatty liver tissues as a direct result of excess lipid availability and accumulation.

Metabolic Alterations and Increased Liver mTOR Expression Precede the Development of Autoimmune Disease in a Murine Model of Lupus Erythematosus

Although metabolic syndrome (MS) and systemic lupus erythematosus (SLE) are often associated, a common link has not been identified. Using the BWF1 mouse, which develops MS and SLE, we sought a molecular connection to explain the prevalence of these two diseases in the same individuals. We determined SLE- markers (plasma anti-ds-DNA antibodies, splenic regulatory T cells (Tregs) and cytokines, proteinuria and renal histology) and MS-markers (plasma glucose, non-esterified fatty acids, triglycerides, insulin and leptin, liver triglycerides, visceral adipose tissue, liver and adipose tissue expression of 86 insulin signaling-related genes) in 8-, 16-, 24-, and 36-week old BWF1 and control New-Zealand-White female mice. Up to week 16, BWF1 mice showed MS-markers (hyperleptinemia, hyperinsulinemia, fatty liver and visceral adipose tissue) that disappeared at week 36, when plasma anti-dsDNA antibodies, lupus nephritis and a pro-autoimmune cytokine profile were detected. BWF1 mice had hyperleptinemia and high splenic Tregs till week 16, thereby pointing to leptin resistance, as confirmed by the lack of increased liver P-Tyr-STAT-3. Hyperinsulinemia was associated with a down-regulation of insulin related-genes only in adipose tissue, whereas expression of liver mammalian target of rapamicyn (mTOR) was increased. Although leptin resistance presented early in BWF1 mice can slow-down the progression of autoimmunity, our results suggest that sustained insulin stimulation of organs, such as liver and probably kidneys, facilitates the over-expression and activity of mTOR and the development of SLE.

Effect of Zingiber officinale on fatty liver induced by oxytetracycline in albino rats.

Background: Fatty liver causes were markedly increased in Egyptian people throughout last years. People prefer to use the medicinal plants instead of using chemical compounds because they are cheap and have few side effects compared to chemical compounds. Ginger is a natural dietary rhizome with antioxidative, anti-inflammatory, and anti-carcinogenic activities. The aim of this study was to evaluate the possible potential therapeutic and protective effects of Zingiber officinale (ginger) against oxytetracyclininduced fatty liver in an attempt to understand its mechanism of action, which may pave the way for possible therapeutic applications. Material and Methods: Albino rats were divided into two major groups, 15 rats for each. The first group was divided into three sub-groups: a) control, b) fatty liver group; that was injected intraperitonealy with oxytetracycline (120mg/kg) for three consecutive days and c) ginger treated group; which was treated with ginger water extract (125 mg/kg) for 30 days after fatty liver induction . All animals were scarified after 33 days of the beginning of the experiment. The second group was divided into three subgroups: a) control, b) fatty liver group; that was injected intraperitonealy with oxytetracycline (120 mg/kg) for three consecutive days and c) ginger protective group; which received ginger for 15 days before induction of fatty liver, then sacrificed after induction of fatty liver (3 days). Blood samples were collected for biochemical analysis. Liver specimens were obtained and fixed in 10% formalin for histological study. Results: Fatty liver groups showed high significant increase in serum glucose, cholesterol, triglycerides, LDL cholesterol, ALAT, ASAT, GGT, LDH, urea, creatinine and A/G ratio while total protein, albumin, globulin and HDL cholesterol were significantly decreased compared to control group. These biochemical changes were accompanied with histopathological alterations in fatty liver tissue. The treatment with ginger ameliorated most of the evaluated biochemical parameters and improved the induced degenerative histopathological changes. The pre-treatment with ginger before the induction of fatty liver gave some protection against factors that experimentally induced fatty liver. Conclusion: Ginger as diet additive is recommend for fatty liver patients or those people who have hyperlipidemic family history.

Effect of Zingiber officinale on fatty liver induced by oxytetracycline in albino rats

Background: Fatty liver causes were markedly increased in Egyptian people throughout last years. People prefer to use the medicinal plants instead of using chemical compounds because they are cheap and have few side effects compared to chemical compounds. Ginger is a natural dietary rhizome with antioxidative, anti-inflammatory, and anti-carcinogenic activities. The aim of this study was to evaluate the possible potential therapeutic and protective effects of Zingiber officinale (ginger) against oxytetracyclininduced fatty liver in an attempt to understand its mechanism of action, which may pave the way for possible therapeutic applications. Material and Methods: Albino rats were divided into two major groups, 15 rats for each. The first group was divided into three sub-groups: a) control, b) fatty liver group; that was injected intraperitonealy with oxytetracycline (120mg/kg) for three consecutive days and c) ginger treated group; which was treated with ginger water extract (125 mg/kg) for 30 days after fatty liver induction . All animals were scarified after 33 days of the beginning of the experiment. The second group was divided into three subgroups: a) control, b) fatty liver group; that was injected intraperitonealy with oxytetracycline (120 mg/kg) for three consecutive days and c) ginger protective group; which received ginger for 15 days before induction of fatty liver, then sacrificed after induction of fatty liver (3 days). Blood samples were collected for biochemical analysis. Liver specimens were obtained and fixed in 10% formalin for histological study. Results: Fatty liver groups showed high significant increase in serum glucose, cholesterol, triglycerides, LDL cholesterol, ALAT, ASAT, GGT, LDH, urea, creatinine and A/G ratio while total protein, albumin, globulin and HDL cholesterol were significantly decreased compared to control group. These biochemical changes were accompanied with histopathological alterations in fatty liver tissue. The treatment with ginger ameliorated most of the evaluated biochemical parameters and improved the induced degenerative histopathological changes. The pre-treatment with ginger before the induction of fatty liver gave some protection against factors that experimentally induced fatty liver. Conclusion: Ginger as diet additive is recommend for fatty liver patients or those people who have hyperlipidemic family history.

Diabetes and Nonalcoholic Fatty Liver Disease

Diabetes and Nonalcoholic Fatty Liver Disease

Effect of Cichorium intybus L. on fatty liver induced by oxytetracycline in albino rats.

Background: Fatty liver is now one of the most common diseases in Egypt. People prefer to use the medicinal plants instead of using chemical compounds because they are cheap and have few side effects compared to chemical compounds.The current investigation was carried out to examine the possible potential therapeutic and protective effects of Cichorium intybus (chicory) against oxytetracyclin-induced fatty liver in an attempt to understand its mechanism of action, which may pave the way for possible therapeutic applications. Material and Methods: Albino rats were divided into two major groups, 15 rats for each. The first group was divided into three sub-groups: a) control, b) fatty liver group; that was injected intraperitonealy with oxytetracycline (120mg/kg) for three consecutive days resulting in steatosis and c) chicory treated group; which was treated with chicory water extract (70 mg/kg) for 30 days after fatty liver induction . All animals were scarified after 33 days of the beginning of the experiment. The second group was divided into three subgroups: a) control, b) fatty liver group; that was injected intraperitonealy with oxytetracycline (120mg/kg) for three consecutive days and c) drug protection group; which received chicory for 15 days before induction of fatty liver, then sacrificed after induction of fatty liver (3 days). Blood samples were collected for biochemical analysis. Liver specimens were obtained and fixed in 10% formalin for histological study. Results: Fatty liver groups showed high significant increase in serum glucose, cholesterol, triglycerides, LDL cholesterol, ALAT, ASAT, GGT, LDH, urea, creatinine and A/G ratio while total protein, albumin, globulin and HDL cholesterol were significantly decreased compared to control group. These biochemical changes were accompanied with histopathological alterations in fatty liver tissue. The treatment with chicory ameliorated most of the evaluated biochemical parameters and improved the induced degenerative histopathological changes. The pre-treatment with chicory before the induction of fatty liver gave some protection against factors that experimentally induced fatty liver. Conclusion: Chicory as diet additive is recommend for fatty liver patients or those people who have hyperlipidemic family history.

Fatty liver, abdominal visceral fat, and cardiometabolic risk factors: the Jackson Heart Study.

The goal of this study was to examine whether fatty liver and abdominal visceral adipose tissue (VAT) are jointly associated with cardiometabolic abnormalities. Black participants were from the Jackson Heart Study (n=2882, 65% women) who underwent computed tomography. Fatty liver was measured by liver attenuation in Hounsfield units (LA), and VAT was quantified volumetrically. Cross-sectional associations between LA, VAT, and cardiometabolic risk factors were assessed using linear and logistic regression, and their joint associations were further examined in 4 subgroups: high-LA/low-VAT (n=1704), low-LA/low-VAT (n=422), high-LA/high-VAT (n=436), and low-LA/high-VAT (n=320). Both LA and VAT were associated with most cardiometabolic traits (all P<0.0001), which persisted after additional adjustment for each other (LA, P<0.01-0.0001; VAT, P<0.0001). In bootstrap analyses, the regression coefficient of VAT was significantly greater than LA for triglycerides, high-density lipoprotein cholesterol, impaired glucose, and metabolic syndrome (P=0.009-0.0001). The interaction between LA and VAT was significant for high-density lipoprotein cholesterol (P=0.002), impaired glucose (P=0.003), and metabolic syndrome (P=0.04). Among 4 subgroups, participants with higher VAT and lower LA had higher prevalence of cardiometabolic traits than those with each condition alone. Both fatty liver and VAT are independent correlates of cardiometabolic risk, but the associations are stronger for VAT than for fatty liver.

Diagnosis of an Abdominal Splenosis in a Case of Ambulatory Paraparesis of the Hind Limbs in a Ferret ( Mustela putorius furo)

A 2-year-old spayed female ferret ( Mustela putorius furo) was presented with a 2-day history of ambulatory paraparesis of the hind limbs. On physical examination a mass was palpated in the cranial abdominal region, caudal to the stomach. A complete blood cell count revealed a normocytic normochromic anemia and reactive lymphocytes. A hypoechoic abdominal mass was observed during an ultrasound examination of the abdomen. An exploratory laparotomy was recommended and performed during which a pyramidal mass resembling a lobe of fatty liver tissue, plus omental torsion, was removed. The histopathologic diagnosis of the surgically removed mass was splenosis. The abdominal pain and ambulatory paraparesis resolved after surgery, which suggests that the paraparesis was due to pain. The findings in this report indicate that splenosis should be included as a differential diagnosis when a ferret presents with an abdominal mass and acute abdominal pain.

Alimentary induced fatty liver and adjuvant therapy with effective natural bioactive molecules

Changes of redox-homeostasis generate cytokines, and free radicals influence many intracellular signaling pathways in different liver diseases. Liophylised table beet and carrot powder (GPS Powder Kft. 1361/004/2003BFÁÉÉÁ) containing bioactive components such as betaine, betanins, betaxanthins, flavonoids, polyphenols, glutamine, beta carotene, vitamins and folic acid may produce changes various cellular pathways. Aim: The aim of this study was to determine the protecting effects of bioactive agents of the liophylised table beet and carrot powder on fatty liver in a “short term” experiment. Method: Male Wistar rats were fed with chow with or without high fat (2% cholesterol, 0.5% cholic acid, 20% sunflower oil) and treated with 0.1 or 1 g/bwkg/day natural product for ten days parallel with the feedings. Cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-α mRNA levels were determined using molecular biologic methods. Free radicals, H-donating activity, reducing power and free SH-group concentrations were determined by luminometry and spectrophotometry. Mobilized methyl groups were assayed by over pressure liquid chromatography method in liver homogenates. Results: It was found that the higher dose of the natural product better decreased the induced free radical reactions, cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-α mRNA-levels both in normal and fatty liver tissues. Although treatments failed to exert significant changes in all global antioxidant parameters, mobilized methyl group concentrations were higher after treatments in fatty liver. Favorable tendencies were also noted in the redox-homeostasis of the fatty liver after treatment. Conclusions: As expected, lyophylised table beet and carrot proved to be a “functional food” in rats with alimentary fat induced fatty liver. It cannot be ruled out that this beneficial effect may have clinical relevance. Orv. Hetil., 2011, 152, 1035–1042.

The Effect of Steatosis on Echogenicity of Colorectal Liver Metastases on Intraoperative Ultrasonography

To investigate the association of relative tumor echogenicity and hepatic steatosis in patients undergoing resection of colorectal liver metastases (CRLM). Prospective study. The Johns Hopkins Hospital. A total of 126 patients undergoing liver surgery for CRLM from January 1, 1998, through December 31, 2008, in whom 191 lesions had complete intraoperative ultrasonography images for review and adequate linked pathological data available. The intraoperative ultrasonography images were reviewed and scored for echogenicity (hypoechoic, isoechoic, or hyperechoic). In addition, a histopathologic review of the nontumorous liver tissue was performed, and the extent of steatosis was scored and correlated with tumor echogenicity. Of the patients undergoing surgery, 49 (38.8%) were found to have mild to severe steatosis. Of the 191 total CRLM visualized by intraoperative ultrasonography, 91 (47.6%) were found to be hypoechoic, 65 (34.0%) were isoechoic, and 35 (18.3%) were hyperechoic. In patients with steatosis, lesions were significantly more likely to be hypoechoic when compared with patients without steatosis (odds ratio, 4.17; 95% confidence interval, 1.87-8.47; P = .001). Echogenicity was independent of the cause of steatosis or response to chemotherapy. The echogenicity of CRLM was significantly affected by the presence of liver steatosis, with decreased echogenicity and increased conspicuity of lesions despite overall poorer image quality. These findings might reinforce the usefulness of intraoperative ultrasonography in identifying additional CRLM in patients undergoing surgical therapy, even in those with fatty liver tissue.

Xenon 133 Ventilation Studies as an Alternative for Detecting and Quantifying Fatty Infiltration of the Liver

Xenon 133 Ventilation Studies as an Alternative for Detecting and Quantifying Fatty Infiltration of the Liver

Special stain and X‐ray probe microanalysis of livers with Wilson disease

Primary copper toxicosis due to Wilson disease is clinically complex, often leading to delayed diagnosis. Because the metabolic disorder is frequently complicated by iron overload due to hypoceruloplasminemia, either a special stain or microanalysis has been recommended for liver biopsy specimens. Liver biopsy was performed in three patients in whom Wilson disease was highly suspected. Light microscopic study included rubeanic acid stain for copper and Berlin blue stain for iron. To improve the resolution of ultra-structures and preservation of toxic metals, short-term fixation with a 0.1% osmic acid solution was applied for X-ray probe microanalysis. Their diagnosis was confirmed by genetic study and copper chelation therapy. Two patients at the age of 17 and 23 years, respectively, demonstrated cirrhotic livers surrounded by fibrous septa, while a 7-year-old patient demonstrated fatty liver with mildly expanded portal tracts. Both copper grains stained with rubeanic acid and cuprothionein by microanalysis were found in the cirrhotic livers of aged patients. However, either morphological method failed to detect copper deposition in fatty liver tissues from the young patient. Iron deposits were also found in the cirrhotic livers of aged patients. The molecular basis of Wilson disease was confirmed by gene analysis. All patients responded to copper chelation therapy. A morphological method of special staining or microanalysis improved with a new fixative may be unreliable for detecting diffusely distributed copper in the early stage of Wilson liver disease.

Principal Component Analysis of Direct Matrix-Assisted Laser Desorption/Ionization Mass Spectrometric Data Related to Metabolites of Fatty Liver

Non-alcoholic steatohepatitis (NASH) is a common liver disease. NASH is characterized by fatty liver, along with inflammation. Most people with NASH are not aware of their condition, even though NASH can lead to hepatic cirrhosis. Several approaches have been tested to clarify the pathology of NASH. However, the mechanism of onset of NASH was not well-defined. In this study, a supervised multivariate analysis (principal component analysis) approach using direct matrix-assisted laser desorption/ionization mass spectrometry (dMALDI-MS) was applied to the analysis of metabolites in starvation-induced fatty liver tissue sections. This approach does not require complex pretreatments. We investigated the characteristic dynamics of metabolites in fatty liver. This approach can be applied to the analysis of human biopsy specimens of fatty liver in future studies.

Dietary chitosan improves hypercholesterolemia in rats fed high-fat diets

The hypolipidemic mechanism of chitosan was investigated in male Sprague-Dawley rats. Animals were divided into 5 groups (n = 8): a normal fat control group, a high-fat control group (HF), a positive control group (CR), and 2 chitosan groups (CIS1 and CIS2). Chitosan was fed at the beginning (CIS1) and after 2 weeks (CIS2). A commercial diet with 5% (wt/wt) cellulose (HF), cholestyramine (CR), or chitosan (CIS1, CIS2) was fed for 6 weeks. Chitosan did not affect food intake but decreased body weight gain and significantly increased fecal fat and cholesterol excretion, reduced the lipid level in plasma and liver, increased liver hepatic and lipoprotein lipase activities compared with HF (P < .05), and tended to relieve the degenerated fatty liver tissue. No significant differences in all measurements were found between the CIS1 and CIS2 groups although the CIS1 rats exhibited lower lipid levels compared to those in the CIS2 group. The results suggest that chitosan reduced the absorption of dietary fat and cholesterol in vivo and could effectively improve hypercholesterolemia in rats.

Multinodular focal fatty infiltration of the liver: Atypical imaging findings on delayed T1‐weighted Gd‐BOPTA‐enhanced liver‐specific MR images

We report a case of pathologically confirmed multinodular focal fatty infiltration. MRI was performed after bolus injection of gadobenate dimeglumine (Gd-BOPTA, MultiHance; Bracco, Milan, Italy), a liver-specific paramagnetic, gadolinium (Gd)-based MR contrast agent that concomitantly enables the acquisition of a standard dynamic phase with timing strategies similar to those used for other extracellular fluid contrast agents, followed by a delayed T1-weighted liver-specific phase (the so-called hepatobiliary phase). In the present case, multiple rounded areas of fatty infiltration, although confidently diagnosed using chemical shift sequences due to a significant signal intensity reduction on out-of-phase images, were unexpectedly hypointense during the delayed liver-specific phase of Gd-BOPTA. Reduced Gd-BOPTA concentration during the liver-specific phase is generally correlated with liver malignancy. Since such lesions can be prospectively mistaken for metastatic disease, we performed a hepatic biopsy to establish a definitive diagnosis. Our empirical observations suggest that Gd-BOPTA uptake may be impaired in fatty infiltrated liver tissue. Because at present there is no report evaluating the kinetics of Gd-BOPTA in fatty liver, further studies are needed to specifically investigate this issue.

Lack of UCP2 reduces fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression

Fatty liver is vulnerable to conditions that challenge hepatocellular energy homeostasis. Lipid-laden hepatocytes highly express uncoupling protein-2 (UCP2), a mitochondrial carrier that competes with adenosine triphosphate (ATP) synthesis by mediating proton leak. However, evidence for a link between UCP2 expression and susceptibility of liver to acute injury is lacking. We asked whether absence of UCP2 protects ob/ob mice from Fas-mediated acute liver damage. UCP2-deficient ob/ob mice (ob/ob:ucp2-/-) and UCP2-competent littermates (ob/ob:ucp2+/+) received a single dose of agonistic anti-Fas antibody (Jo2). Low-dose Jo2 (0.15 mg/kg intraperitoneally) caused less serum alanine aminotransferase (ALT) elevation and lower apoptosis rates in ob/ob:ucp2-/- mice. High-dose Jo2 (0.40 mg/kg intraperitoneally) proved uniformly fatal; however, ob/ob:ucp2-/- mice survived longer with less depletion of liver ATP stores, indicating that fatty hepatocytes may benefit from lack of UCP2 during Jo2 challenge. Although UCP2 reportedly controls mitochondrial oxidant production, its absence had no apparent effect on fatty liver tissue malondialdehyde levels augmented by Jo2. This finding prompted us to determine UCP2 expression in Kupffer cells, a major source of intrahepatic oxidative stress. UCP2 expression was found diminished in Kupffer cells of untreated ob/ob:ucp2+/+ mice, conceivably contributing to increased oxidative stress in fatty liver and limiting the impact of UCP2 ablation. In conclusion, whereas UCP2 abundance in fatty hepatocytes exacerbates Fas-mediated injury by compromising ATP stores, downregulation of UCP2 in Kupffer cells may account for persistent oxidative stress in fatty liver. Our data support a cell-specific approach when considering the therapeutic effects of mitochondrial uncoupling in fatty liver disease.