DLK1/PREF1 regulates nutrient metabolism and protects from steatosis
Marika CharalambousSimão Teixeira da RochaElizabeth J. RadfordGema Medina‐GómezScott CurranScarlett B. PinnockSacri R. FerrónAntonio Vidal‐PuigAnne C. Ferguson‐Smith
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Abstract:
Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and obesity, as well as progressive liver dysfunction. Recent animal studies have underscored the importance of hepatic growth hormone (GH) signaling in the development of NAFLD. The imprinted Delta-like homolog 1 (Dlk1)/preadipocyte factor 1 (Pref1) gene encodes a complex protein producing both circulating and membrane-tethered isoforms whose expression dosage is functionally important because even modest elevation during embryogenesis causes lethality. DLK1 is up-regulated during embryogenesis, during suckling, and in the mother during pregnancy. We investigated the normal role for elevated DLK1 dosage by overexpressing Dlk1 from endogenous control elements. This increased DLK1 dosage caused improved glucose tolerance with no primary defect in adipose tissue expansion even under extreme metabolic stress. Rather, Dlk1 overexpression caused reduced fat stores, pituitary insulin-like growth factor 1 (IGF1) resistance, and a defect in feedback regulation of GH. Increased circulatory GH culminated in a switch in whole body fuel metabolism and a reduction in hepatic steatosis. We propose that the function of DLK1 is to shift the metabolic mode of the organism toward peripheral lipid oxidation and away from lipid storage, thus mediating important physiological adaptations associated with early life and with implications for metabolic disease resistance.Keywords:
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Steatosis
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Liver enzyme
Elevated liver enzymes
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PNPLA3 and MTP genes have been associated with liver steatosis and chronic hepatitis C. We studied the influence of MTP and PNPLA3 polymorphisms in 114 Italian patients with chronic hepatitis C, evaluating the histological and clinical presentation of liver disease. The study confirmed the association of PNPLA3 polymorphisms with liver steatosis (p=0.041), but did not show any additive effect of MTP polymorphisms in the development of steatosis. MTP polymorphisms do not seem to influence PNPLA3 in the development of liver steatosis. Further studies with a larger number of patients are required.
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Objectives: This study describes the characteristics of hepatic steatosis on ultrasound imaging by grading of Hagen - Assert. Determining the factors related with fatty liver. Methodology: Cross-sectional study. Results: By studying 448 patients went to general examination at Hue University Hospital from 1/5/2013 to 1/9/2013, we have some of comments: 76.1% of patients has hepatic steatosis on ultrasound imaging in the aged of 30-60 years, common in men than women,with male – female ratio:1.23. The majority (96%) hepatic steatosis was complete all lobes, and the remaining 4% patient was focal fatty liver. Grading hepatic steatosis by Hagen-Ansert classification (1995): there were 66.5% grade 1, 30.5% grade 2, and grade 3 of 3.0%. 26 - 32% patients’ hepatic steatosis on ultrasound combinated with increasing of Lipidemia (Cholesterol, Triglycerid and LDL Cholesterol). Conclusion: There were 66.5% patients grading level 1 by Hagen-Ansert classification for hepatic steatosis. Increasing of Lipidemia index represented only 26 – 32% of patients. Our study did not found significant compatible change between the hepatic steatosis on ultrasound imaging and Triglycerid blood concentrations (p > 0.05). Keywords: Image, ultrasound, hepatic steatosis, fatty liver
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ABSTRACT Objectives: To determine the inter observer agreement of ultrasound diagnosis of the severity and grading of steatosis in patients with HCV Methods: Patients with HCV were evaluated, from March 2008-August 2010 at Radiology department, Dow Medical College and Civil Hospital Karachi, with ultrasound for detection and grading of steatosis and fibrosis using a standardized set of criteria. The same sets of images were reviewed by the same radiologists 5 years later (2015) for determining the agreement in the grading. Kappa (k) statistics were utilized. Present results were compared with that of the pilot study conducted in 2007 on 100 images. Results: 452 set of images were reviewed by three radiologists, designated A, B and C. The inter observer agreement was satisfactory to good with k=0.8 for no steatosis, 0.4 for mild steatosis, 0.7 for moderate steatosis and 0.9 for severe steatosis. The inter-observer agreement in the pilot study in 2007 had shown k – values of 0.81 for no steatosis, 0.5 for mild steatosis, 0.8 for moderate steatosis and 0.9 for severe steatosis. Conclusions: The studied criteria for ultrasound diagnosis and grading of hepatic steatosis had persistently good inter-observer agreement for absence, and moderate to severe grades of steatosis. The agreement was low for mild steatosis. Key words: Fatty liver, Hepatic steatosis, ultrasound, diagnosis, grading, Inter observer agreement.
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The present study has developed and evaluated the effectiveness of a new echo attenuation measurement function combined with an ultrasonic diagnostic system for the accurate diagnosis of liver steatosis.A multicenter prospective study involving patients with chronic hepatitis was carried out. All patients underwent liver biopsy, and attenuation coefficient (ATT) was measured on the same day. The fat area (%) of biopsy specimens was quantitatively evaluated. Correlations between ATT, steatosis grade, and fat area were evaluated.A total of 351 patients were enrolled in this study. The median values of fat area for steatosis grades S0, S1, S2, and S3 were 0.6%, 3.2%, 6.4%, and 15.5%, respectively. A significant correlation was found between fat area and steatosis grade (P < 0.001). Similarly, the median values of ATT for steatosis grades S0, S1, S2, and S3 were 0.55, 0.63, 0.69, and 0.85 dB/cm/MHz, respectively, and ATT increased with an increase in the steatosis grade (P < 0.001). Attenuation coefficient was significantly correlated with fat area (r = 0.50, P < 0.001). The area under the receiver operating characteristic curve corresponding to S ≥ 1, S ≥ 2, and S ≥ 3 were 0.79, 0.87, and 0.96, respectively. Similarly, the sensitivity and specificity of S ≥ 1, S ≥ 2, and S ≥ 3 were 72%, 82%, and 87% and 72%, 82%, and 89%, respectively.The newly developed ATT measurement for evaluation of liver steatosis was closely correlated with steatosis grade and automated quantification of fat area, and it provides clinically relevant information.
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Attenuation imaging (ATI) is a method to quantitatively assess steatosis by using fat attenuation technique that is installed on Aplio i800, an all-purpose ultrasound diagnostic device (Toshiba Medical Systems). We assessed the correlation between Controlled Attenuation Parameter (CAP) and ATI in 116 patients with chronic hepatitis. Two methods showed excellent correlation (Pearson's r=0.699, 95% CI 0.592-0.782). ATI can be used as a method to assess steatosis without a device dedicated to ATI method.
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