Browsing by Subject "Hepatic steatosis"

Now showing 1 - 8 of 8
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    The Association Between Nonalcoholic Fatty Liver Disease and Metabolic Abnormalities in The United States Population
    (Wolters Kluwer, 2017-02) Jinjuvadia, Raxitkumar; Antaki, Fadi; Lohia, Prateek; Liangpunsakul, Suthat; Medicine, School of Medicine
    BACKGROUND: Prevalence of nonalcoholic fatty liver disease (NAFLD) and rate of advanced fibrosis among individuals with metabolic syndrome (MetS) and its individual metabolic abnormalities needs better understanding in the United States population. We aim to study these by using a large United States population database, the Third National Health and Nutrition Examination Survey (NHANES III). METHODS: A total of 11,674 individuals were included in our study cohort. NAFLD was defined as presence of moderate to severe hepatic steatosis on liver ultrasound in absence of viral hepatitis, significant alcohol use, elevated transferrin level, and medication use leading to hepatic steatosis. Advanced fibrosis among those with NAFLD was determined using noninvasive method, the NAFLD fibrosis score. MetS was defined based on the National Cholesterol Education Program Adult Treatment Panel III definition. RESULTS: The prevalence of NAFLD among included study cohort was 18.2% (95% confidence interval, 16.5-19.9). Individuals with metabolic abnormalities demonstrated higher prevalence (MetS, 43.2%; increased waist circumference, 31.2%; impaired fasting glucose/diabetes, 41.2%; high triglyceride level, 34.7%; low high-density lipoprotein, 27.8%; high blood pressure, 29.2%). The individuals with MetS had significantly higher NAFLD prevalence compared with controls (adjusted odds ratio, 11.5; 95% confidence interval, 8.9-14.7). The severity of hepatic steatosis was also noted to increase with higher number of metabolic abnormalities. Among individual metabolic abnormalities, increased waist circumference, impaired fasting glucose/diabetes, high triglyceride, and low high-density lipoprotein levels were found to be independently associated with NAFLD. Individuals with impaired fasting glucose/diabetes and those with 5 metabolic abnormalities had higher rate of advanced fibrosis (18.6% and 30.3%, respectively). Prevalence of NAFLD among individuals without any metabolic abnormality was 6.1%. CONCLUSION: Prevalence of NAFLD and rate of advanced fibrosis are significantly high among individuals with metabolic abnormalities.
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    Comparative study of the modulation of fructose/sucrose-induced hepatic steatosis by mixed lipid formulations varying in unsaturated fatty acid content
    (Springer (Biomed Central Ltd.), 2015) Siddiqui, Rafat A.; Xu, Zhidong; Harvey, Kevin A.; Pavlina, Thomas M.; Becker, Michael J.; Zaloga, Gary P.; Department of Medicine, IU School of Medicine
    BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries. NAFLD encompasses a spectrum of diseases, ranging from hepatic steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and liver failure. The etiology of NAFLD remains unclear but is thought to relate to increased fatty acid flux within the liver that results in toxic fatty acid metabolite production. One source of increased fatty acid flux is fructose/sucrose-induced hepatic lipogenesis. Current treatment for NAFLD encompasses dietary modifications. However, little scientific evidence exists on which to base many dietary recommendations, especially the intake of different types of carbohydrates and fats. We hypothesized that lipid mixtures of unsaturated fatty acids would inhibit lipogenesis and subsequent hepatic steatosis induced by high carbohydrate diets. The aim of this study was to examine the effects of different complex mixtures of fatty acids upon the development of fructose/sucrose-induced hepatic steatosis. METHODS: C57BL/6 mice were randomized to normocaloric chow-based diets that varied in the type of carbohydrate (starch, sucrose, fructose). Animals in each carbohydrate group were further randomized to diets that varied in lipid type (no additional lipid, soybean oil, fish oil, olive/soybean oil, macadamia nut oil). These oils were chosen based upon their content of omega-6 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, omega-9 monounsaturated fatty acids, or omega-7 monounsaturated fatty acids. Fatty acid flux in the liver was determine by assessing hepatic lipid content (steatosis). We also assessed fatty acid levels in the plasma and liver of the animals, hepatic lipogenesis activity, hepatic stearoyl-CoA-1 desaturase activity, and hepatic elongase activity. RESULTS: Animals consumed similar amounts of the diets and maintained normal body weights throughout the study. Both sucrose and fructose induced hepatic lipogenesis and steatosis, with fructose being more potent. All mixed lipids similarly inhibited steatosis, limiting lipid content to levels found in the control (starch) animals. Lipogenesis and stearoyl-CoA-1 desaturase activity were increased in the sucrose and fructose groups. Levels of these enzymatic processes remained at baseline in all of the lipid groups. CONCLUSION: This is the first study to compare various complex lipid mixtures, based upon dietary oils with different types of long-chain fatty acids, upon development of sucrose/fructose-induced steatosis. Both carbohydrate source and lipid content appear important for the modulation of steatosis. Moderate intake of complex lipids with high unsaturated to saturated fatty acid ratios inhibited both lipogenesis and steatosis.
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    Disturbances in the murine hepatic circadian clock in alcohol-induced hepatic steatosis
    (Springer Nature, 2014-01-16) Zhou, Peng; Ross, Ruth A.; Pywell, Cameron M.; Liangpunsakul, Suthat; Duffield, Giles E.; Medicine, School of Medicine
    To investigate the role of the circadian clock in the development of alcohol-induced fatty liver disease we examined livers of mice chronically alcohol-fed over 4-weeks that resulted in steatosis. Here we show time-of-day specific changes in expression of clock genes and clock-controlled genes, including those associated with lipid and bile acid regulation. Such changes were not observed following a 1-week alcohol treatment with no hepatic lipid accumulation. Real-time bioluminescence reporting of PERIOD2 protein expression suggests that these changes occur independently of the suprachiasmatic nucleus pacemaker. Further, we find profound time-of-day specific changes to the rhythmic synthesis/accumulation of triglycerides, cholesterol and bile acid, and the NAD/NADH ratio, processes that are under clock control. These results highlight not only that the circadian timekeeping system is disturbed in the alcohol-induced hepatic steatosis state, but also that the effects of alcohol upon the clock itself may actually contribute to the development of hepatic steatosis.
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    FOXO transcription factors protect against the diet-induced fatty liver disease
    (SpringerNature, 2017-03-16) Pan, Xiaoyan; Zhang, Yang; Kim, Hyeong-Geug; Liangpunsakul, Suthat; Dong, X. Charlie; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Forkhead O transcription factors (FOXOs) have been implicated in glucose and lipid homeostasis; however, the role of FOXOs in the development of nonalcoholic fatty liver disease (NAFLD) is not well understood. In this study, we designed experiments to examine the effects of two different diets-very high fat diet (HFD) and moderately high fat plus cholesterol diet (HFC)-on wildtype (WT) and liver-specific Foxo1/3/4 triple knockout mice (LTKO). Both diets induced severe hepatic steatosis in the LTKO mice as compared to WT controls. However, the HFC diet led to more severe liver injury and fibrosis compared to the HFD diet. At the molecular levels, hepatic Foxo1/3/4 deficiency triggered a significant increase in the expression of inflammatory and fibrotic genes including Emr1, Ccl2, Col1a1, Tgfb, Pdgfrb, and Timp1. Thus, our data suggest that FOXO transcription factors play a salutary role in the protection against the diet-induced fatty liver disease.
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    Hepatic Steatosis After Neoadjuvant Chemotherapy for Pancreatic Cancer: Incidence and Implications for Outcomes After Pancreatoduodenectomy
    (Springer Nature, 2020-07-15) Flick, K.F.; Al-Temimi, M.H.; Maataman, T.K.; Sublette, C.M.; Swensson, J.K.; Nakeeb, A.; Ceppa, C.P.; Nguyen, T.K.; Schmidt, C.M.; Zyromski, N.J.; Tann, M.A.; House, M.G.; Surgery, School of Medicine
    Background This study aimed to determine the incidence of new onset hepatic steatosis after neoadjuvant chemotherapy for pancreatic cancer and its impact on outcomes after pancreatoduodenectomy. Methods Retrospective review identified patients who received neoadjuvant chemotherapy for pancreatic adenocarcinoma and underwent pancreatoduodenectomy from 2013 to 2018. Preoperative computed tomography scans were evaluated for the development of hepatic steatosis after neoadjuvant chemotherapy. Hypoattenuation included liver attenuation greater than or equal to 10 Hounsfield units less than tissue density of spleen on noncontrast computed tomography and greater than or equal to 20 Hounsfield units less on contrast-enhanced computed tomography. Results One hundred forty-nine patients received neoadjuvant chemotherapy for a median of 5 cycles (interquartile range (IQR), 4–6). FOLFIRINOX was the regimen in 78% of patients. Hepatic steatosis developed in 36 (24%) patients. The median time from neoadjuvant chemotherapy completion to pancreatoduodenectomy was 40 days (IQR, 29–51). Preoperative biliary stenting was performed in 126 (86%) patients. Neoadjuvant radiotherapy was delivered to 23 (15%) patients. Female gender, obesity, and prolonged exposure to chemotherapy were identified as risk factors for chemotherapy-associated hepatic steatosis. Compared with control patients without neoadjuvant chemotherapy-associated hepatic steatosis, patients developing steatosis had similar rates of postoperative pancreatic fistula (8% (control) vs. 4%, p = 0.3), delayed gastric emptying (8% vs. 14%, p = 0.4), and major morbidity (11% vs. 15%, p = 0.6). Ninety-day mortality was similar between groups (8% vs. 2%, p = 0.08). Conclusion Hepatic steatosis developed in 24% of patients who received neoadjuvant chemotherapy but was not associated with increased morbidity or mortality after pancreatoduodenectomy.
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    Knockout of secretin ameliorates biliary and liver phenotypes during alcohol-induced hepatotoxicity
    (BMC, 2023-01-09) Kyritsi, Konstantina; Wu, Nan; Zhou, Tianhao; Carpino, Guido; Baiocchi, Leonardo; Kennedy, Lindsey; Chen, Lixian; Ceci, Ludovica; Meyer, Alison Ann; Barupala, Nipuni; Franchitto, Antonio; Onori, Paolo; Ekser, Burcin; Gaudio, Eugenio; Wu, Chaodong; Marakovits, Corinn; Chakraborty, Sanjukta; Francis, Heather; Glaser, Shannon; Alpini, Gianfranco; Medicine, School of Medicine
    Background: Alcohol-related liver disease (ALD) is characterized by ductular reaction (DR), liver inflammation, steatosis, fibrosis, and cirrhosis. The secretin (Sct)/secretin receptor (SR) axis (expressed only by cholangiocytes) regulates liver phenotypes in cholestasis. We evaluated the role of Sct signaling on ALD phenotypes. Methods: We used male wild-type and Sct-/- mice fed a control diet (CD) or ethanol (EtOH) for 8 wk. Changes in liver phenotypes were measured in mice, female/male healthy controls, and patients with alcoholic cirrhosis. Since Cyp4a10 and Cyp4a11/22 regulate EtOH liver metabolism, we measured their expression in mouse/human liver. We evaluated: (i) the immunoreactivity of the lipogenesis enzyme elongation of very-long-chain fatty acids 1 (Elovl, mainly expressed by hepatocytes) in mouse/human liver sections by immunostaining; (ii) the expression of miR-125b (that is downregulated in cholestasis by Sct) in mouse liver by qPCR; and (iii) total bile acid (BA) levels in mouse liver by enzymatic assay, and the mRNA expression of genes regulating BA synthesis (cholesterol 7a-hydroxylase, Cyp27a1, 12a-hydroxylase, Cyp8b1, and oxysterol 7a-hydroxylase, Cyp7b11) and transport (bile salt export pump, Bsep, Na+-taurocholate cotransporting polypeptide, NTCP, and the organic solute transporter alpha (OSTa) in mouse liver by qPCR. Results: In EtOH-fed WT mice there was increased biliary and liver damage compared to control mice, but decreased miR-125b expression, phenotypes that were blunted in EtOH-fed Sct-/- mice. The expression of Cyp4a10 increased in cholangiocytes and hepatocytes from EtOH-fed WT compared to control mice but decreased in EtOH-fed Sct-/- mice. There was increased immunoreactivity of Cyp4a11/22 in patients with alcoholic cirrhosis compared to controls. The expression of miR-125b decreased in EtOH-fed WT mice but returned at normal values in EtOH-fed Sct-/- mice. Elovl1 immunoreactivity increased in patients with alcoholic cirrhosis compared to controls. There was no difference in BA levels between WT mice fed CD or EtOH; BA levels decreased in EtOH-fed Sct-/- compared to EtOH-fed WT mice. There was increased expression of Cyp27a1, Cyp8b1, Cyp7b1, Bsep, NTCP and Osta in total liver from EtOH-fed WT compared to control mice, which decreased in EtOH-fed Sct-/- compared to EtOH-fed WT mice. Conclusions: Targeting Sct/SR signaling may be important for modulating ALD phenotypes.
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    Pyruvate Dehydrogenase Kinase 4 Deficiency and Hepatic Steatosis
    (2009-06-23T21:37:16Z) Hwang, Byounghoon; Harris, Robert A.; Roach, Peter J.; Thurmond, Debbie C.; Elmendorf, Jeffrey S.; Considine, Robert V.
    Regulation of the pyruvate dehydrogenase complex (PDC) is important for glucose homeostasis and control of fuel selection by tissues. Knocking out pyruvate dehydrogenase kinase 4 (PDK4), one of four kinases responsible for regulation of PDC activity, lowers blood glucose levels by limiting the supply of three carbon compounds for gluconeogenesis. Down regulation of PDK4 expression is also important for control of blood glucose by insulin. The primary goal was to determine whether PDK4 should be considered a target for the treatment of diabetes. A major concern is that inhibition of fatty acid oxidation by PDK4 deficiency may promote fat accumulation in tissues and worsen insulin sensitivity. This was examined by feeding wild type and PDK4 knockout mice a diet rich in saturated fat. Fasting blood glucose levels were lower, glucose tolerance was better, insulin sensitivity was greater, and liver fat was reduced in PDK4 knockout mice. The reduction in liver fat is contradictory to the finding that fibrate drugs increase PDK4 expression but ameliorate hepatic steatosis in rodents. To investigate this phenomenon, wild type and PDK4 knockout mice were fed the high saturated fat diet with and without clofibric acid. The beneficial effect of clofibric acid on hepatic steatosis was greater in the PDK4 knockout mice, indicating up regulation of PDK4 is not necessary and likely opposes the effect of clofibric acid on hepatic steatosis. Clofibric acid dramatically lowered the amount of hepatic CD36, a plasma membrane translocase required for fatty acid import, suggesting a novel mechanism for prevention of hepatic steatosis by fibrates. PDK4 deficiency had no effect on CD36 expression but reduced the enzymatic capacity for fatty acid synthesis, suggesting clofibric acid and PDK4 deficiency ameliorate hepatic steatosis by independent mechanisms. Investigation of the mechanism by which insulin regulates PDK4 expression revealed a novel binding site for hepatic nuclear factor 4α (HNF4α) in the PDK4 promoter. The stimulatory effect of HNF4α was sensitive to inhibition by Akt which is activated by insulin. The findings suggest PDK4 is a viable target for the treatment of hepatic steatosis and type 2 diabetes.
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    Use of a crossed high alcohol preferring (cHAP) mouse model with the NIAAA-model of chronic-binge ethanol intake to study liver injury
    (Oxford University Press, 2017-11-01) Thompson, Kyle J.; Nazari, Shayan S.; Jacobs, W. Carl; Grahame, Nicholas J.; McKillop, Iain H.; Psychology, School of Science
    Aims: This study sought to compare mice bred to preferentially consume high amounts of alcohol (crossed-high alcohol preferring, cHAP) to c57BL/6 (C57) mice using a chronic-binge ethanol ingestion model to induce alcoholic liver disease (ALD). Methods: Male C57 and cHAP mice were randomized to a Lieber-DeCarli control (LDC) diet, Lieber-DeCarli 5% (v/v) ethanol (LDE) diet or free-choice between 10% (v/v) ethanol in drinking water (EtOH-DW) and DW. After 4 weeks mice were gavaged with either 9 g/kg maltose-dextrin (LDC+MD) or 5 g/kg EtOH (LDE+Binge, EtOH-DW+Binge). Nine hours later tissue and serum were collected and analyzed. Results: cHAP mice on EtOH-DW consumed significantly more ethanol than cHAP or C57 mice maintained on LDE. However, cHAP and C57 mice on the LDE+Binge regiment had greater hepatosteatosis and overall degree of liver injury compared to EtOH-DW+Binge. Changes in pro-inflammatory gene expression was more pronounced in cHAP mice than C57 mice. Analysis of liver enzymes revealed a robust induction of CYP2E1 in C57 and cHAP mice maintained on EtOH-DW+Binge or LDE+Binge. However, while C57 mice exhibited higher basal hepatic glutathione than cHAP mice, these mice appeared more susceptible to oxidative stress following LDE+Binge than cHAP counterparts. Conclusions: Despite cHAP mice consuming more total ethanol prior to gavage when maintained on EtOH-DW, LDE followed by gavage created a more severe model of ALD in both C57 and cHAP mice. These data suggest factors other than total amount of alcohol consumed affect degree of ALD development in the chronic-binge model in cHAP mice. Short summary: cHAP mice voluntarily consume high amounts of ethanol and exhibited hepatic injury when subject to chronic-binge ethanol feeding with the Lieber-DeCarli diet. However, hepatic injury was reduced in cHAP mice in a chronic-binge model following voluntary high ethanol consumption in drinking water.