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Vitamin E sequestration by liver fat in humans.
Violet, PC, Ebenuwa, IC, Wang, Y, Niyyati, M, Padayatty, SJ, Head, B, Wilkins, K, Chung, S, Thakur, V, Ulatowski, L, et al
JCI insight. 2020;(1)
Abstract
BACKGROUNDWe hypothesized that obesity-associated hepatosteatosis is a pathophysiological chemical depot for fat-soluble vitamins and altered normal physiology. Using α-tocopherol (vitamin E) as a model vitamin, pharmacokinetics and kinetics principles were used to determine whether excess liver fat sequestered α-tocopherol in women with obesity-associated hepatosteatosis versus healthy controls.METHODSCustom-synthesized deuterated α-tocopherols (d3- and d6-α-tocopherols) were administered to hospitalized healthy women and women with hepatosteatosis under investigational new drug guidelines. Fluorescently labeled α-tocopherol was custom-synthesized for cell studies.RESULTSIn healthy subjects, 85% of intravenous d6-α-tocopherol disappeared from the circulation within 20 minutes but reappeared within minutes and peaked at 3-4 hours; d3- and d6-α-tocopherols localized to lipoproteins. Lipoprotein redistribution occurred only in vivo within 1 hour, indicating a key role of the liver in uptake and re-release. Compared with healthy subjects who received 2 mg, subjects with hepatosteatosis had similar d6-α-tocopherol entry rates into liver but reduced initial release rates (P < 0.001). Similarly, pharmacokinetics parameters were reduced in hepatosteatosis subjects, indicating reduced hepatic d6-α-tocopherol output. Reductions in kinetics and pharmacokinetics parameters in hepatosteatosis subjects who received 2 mg were echoed by similar reductions in healthy subjects when comparing 5- and 2-mg doses. In vitro, fluorescent-labeled α-tocopherol localized to lipid in fat-loaded hepatocytes, indicating sequestration.CONCLUSIONSThe unique role of the liver in vitamin E physiology is dysregulated by excess liver fat. Obesity-associated hepatosteatosis may produce unrecognized hepatic vitamin E sequestration, which might subsequently drive liver disease. Our findings raise the possibility that hepatosteatosis may similarly alter hepatic physiology of other fat-soluble vitamins.TRIAL REGISTRATIONClinicalTrials.gov, NCT00862433.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases and NIH grants DK053213-13, DK067494, and DK081761.
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Exacerbation of insulin resistance and hepatic steatosis deriving from zinc deficiency in patients with HCV-related chronic liver disease.
Himoto, T, Nomura, T, Tani, J, Miyoshi, H, Morishita, A, Yoneyama, H, Haba, R, Masugata, H, Masaki, T
Biological trace element research. 2015;(1-2):81-8
Abstract
The role of zinc (Zn) in hepatic steatosis of patients with HCV-related chronic liver disease (CLD-C) remains uncertain, although persistent HCV infection often evokes hepatic steatosis. The primary purpose of this study was to elucidate the contribution of Zn deficiency to hepatic steatosis in patients with CLD-C. Fifty nondiabetic patients with CLD-C were enrolled. Hepatic 4-hydroxy-2-nonenal (4-HNE) expression was examined using an immunohistochemical procedure as a marker for lipid peroxidation. Serum ferritin levels were assessed for iron overload. Insulin resistance was evaluated using the values of the homeostasis model for assessment of insulin resistance (HOMA-IR). The severity of hepatic steatosis was graded on the classification system proposed by Brunt and colleagues. Serum Zn levels were inversely correlated with serum ferritin levels in the patients with CLD-C (r = -0.382, p = 0.0062). Serum ferritin levels were strongly associated with the HOMA-IR values (r = 0.476, p = 0.0005). Therefore, Zn deficiency resulted in insulin resistance through iron overload. Moreover, serum Zn levels were significantly decreased in proportion to the level of hepatic 4-HNE expression, which was enhanced as hepatic steatosis developed. Then, Zn deficiency eventually seemed to exacerbate hepatic steatosis by way of an increase in lipid peroxidation. However, the serum Zn levels were not associated with either loads of HCV-RNA or HCV genotypes. These data suggest that, in patients with CLD-C, Zn deficiency promotes insulin resistance by exacerbating iron overload in the liver and induces hepatic steatosis by facilitating lipid peroxidation.
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Short-term multidisciplinary non-pharmacological intervention is effective in reducing liver fat content assessed non-invasively in patients with nonalcoholic fatty liver disease (NAFLD).
Scaglioni, F, Marino, M, Ciccia, S, Procaccini, A, Busacchi, M, Loria, P, Lonardo, A, Malavolti, M, Battistini, NC, Pellegrini, M, et al
Clinics and research in hepatology and gastroenterology. 2013;(4):353-8
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to steatohepatitis, and cirrhosis in patients with alcohol intake less than 20 g/day, and is usually associated with insulin resistance (IR). AIM: Given that no drugs are specifically approved for NAFLD, we tested the efficacy of a non-pharmacological multidisciplinary intervention based on a personalized diet, physical activity and behavior therapy. METHODS In this open non-randomized study, personalized diet, physical exercise and behaviour therapy for 3 months were prescribed in 12 consecutive patients with NAFLD. Lifestyle, including total caloric intake, physical activity and resting energy expenditure was monitored by a SenseWear Armband. Insulin Resistance (IR) was measured by HOMA and oral glucose insulin sensitivity tests (OGIS); fat liver content was estimated by two different semi-quantitative scores and by the Doppler Power Index (DPI). RESULTS Data show that the multidisciplinary intervention produced a significant reduction of total caloric intake, a 8% reduction in body weight, a modest increase in daily physical activity, a significant (P<0.001) reduction of aminotransferases and a decrease of total hepatic fat content. CONCLUSIONS A 3-month multidisciplinary intervention inducing at least 8% of weight loss, improves liver tests and decreases liver fat content.
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The value of pre-operative magnetic resonance spectroscopy in the assessment of steatohepatitis in patients with colorectal liver metastasis.
Urdzik, J, Bjerner, T, Wanders, A, Weis, J, Duraj, F, Haglund, U, Norén, A
Journal of hepatology. 2012;(3):640-6
Abstract
BACKGROUND & AIMS Neoadjuvant chemotherapy prior to liver surgery for colorectal metastases can cause marked steatosis (≥ 33%) and steatohepatitis defined by non-alcoholic fatty liver disease activity score (NAS) as adverse effects on liver parenchyma. The aim of this study was to evaluate the steatosis level prior to liver resection using proton magnetic resonance spectroscopy ((1)H MRS) and to compare it with digital quantification of steatosis (DQS) and "classical" histopathology. METHODS (1)H MRS at 3T evaluated steatosis in 35 patients with colorectal liver metastasis, planned for liver resection. Non-tumorous liver parenchyma samples were obtained after surgery for classical histopathology and DQS utilising automated software for quantification of histopathological slides using image processing. RESULTS Classical histopathology defined marked steatosis in nine patients. Histopathology was less reliable than DQS (interclass correlation coefficient - ICC 0.771) or (1)H MRS (ICC 0.722) in steatosis estimation. (1)H MRS showed very similar steatosis levels and high reliability compared to DQS (ICC 0.955). Steatohepatitis was observed in seven patients (NAS ≥ 4) and (1)H MRS was able to predict it with 100% sensitivity and 89% specificity at threshold 10.9%, without knowing lobular inflammation or hepatocyte ballooning. BMI was significantly higher in the groups with marked steatosis and steatohepatitis. Standard blood tests or chemotherapy had no predictive value. CONCLUSIONS (1)H MRS is a reliable non-invasive tool for steatosis assessment, and interestingly, it was able to predict steatohepatitis defined by NAS ≥ 4 in patients planned for liver resection of colorectal metastases after neoadjuvant chemotherapy.
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Association of pericardial fat with liver fat and insulin sensitivity after diet-induced weight loss in overweight women.
Bosy-Westphal, A, Kossel, E, Goele, K, Blöcker, T, Lagerpusch, M, Later, W, Heller, M, Glüer, CC, Müller, MJ
Obesity (Silver Spring, Md.). 2010;(11):2111-7
Abstract
Pericardial adipose tissue (PAT) is positively associated with fatty liver and obesity-related insulin resistance. Because PAT is a well-known marker of visceral adiposity, we investigated the impact of weight loss on PAT and its relationship with liver fat and insulin sensitivity independently of body fat distribution. Thirty overweight nondiabetic women (BMI 28.2-46.8 kg/m(2), 22-41 years) followed a 14.2 ± 4-weeks low-calorie diet. PAT, abdominal subcutaneous (SAT), and visceral fat volumes (VAT) were measured by magnetic resonance imaging (MRI), total fat mass, trunk, and leg fat by dual-energy X-ray absorptiometry and intrahepatocellular lipids (IHCL) by ((1))H-magnetic resonance spectroscopy. Euglycemic hyperinsulinemic clamp (M) and homeostasis model assessment of insulin resistance (HOMA(IR)) were used to assess insulin sensitivity or insulin resistance. At baseline, PAT correlated with VAT (r = 0.82; P < 0.001), IHCL (r = 0.46), HOMA(IR) (r = 0.46), and M value (r = -0.40; all P < 0.05). During intervention, body weight decreased by -8.5%, accompanied by decreases of -12% PAT, -13% VAT, -44% IHCL, -10% HOMA2-%B, and +24% as well as +15% increases in HOMA2-%S and M, respectively. Decreases in PAT were only correlated with baseline PAT and the loss in VAT (r = -0.56; P < 0.01; r = 0.42; P < 0.05) but no associations with liver fat or indexes of insulin sensitivity were observed. Improvements in HOMA(IR) and HOMA2-%B were only related to the decrease in IHCL (r = 0.62, P < 0.01; r = 0.65, P = 0.002) and decreases in IHCL only correlated with the decrease in VAT (r = 0.61, P = 0.004). In conclusion, cross-sectionally PAT is correlated with VAT, liver fat, and insulin resistance. Longitudinally, the association between PAT and insulin resistance was lost suggesting no causal relationship between the two.
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A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis.
Schwimmer, JB, Middleton, MS, Deutsch, R, Lavine, JE
Alimentary pharmacology & therapeutics. 2005;(7):871-9
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BACKGROUND Children with non-alcoholic steatohepatitis are insulin-resistant and metformin has been proposed as a potential therapy. However, paediatric safety and efficacy data are absent. AIM: To test the hypothesis that metformin therapy will safely improve markers of liver disease in paediatric non-alcoholic steatohepatitis. METHODS Single-arm open-label pilot study of metformin 500 mg twice daily for 24 weeks in non-diabetic children with biopsy-proven non-alcoholic steatohepatitis. RESULTS Ten obese children (mean body mass index 30.4) enrolled and completed the trial. Mean alanine aminotransferase and aspartate aminotransferase (AST) improved significantly (P < 0.01) from baseline (184, 114 U/L) to end of treatment (98, 68 U/L). Alanine aminotransferase normalized in 40% and AST normalized in 50% of subjects. Children demonstrated significant improvements in liver fat measured by magnetic resonance spectroscopy (30-23%, P < 0.01); insulin sensitivity measured by quantitative insulin sensitivity check index (0.294-0.310, P < 0.05); and quality of life measured by pediatric quality of life inventory 4.0 (69-81, P < 0.01). CONCLUSION Open-label treatment with metformin for 24 weeks was notable for improvement in liver chemistry, liver fat, insulin sensitivity and quality of life. A large randomized-controlled trial is needed to definitively determine the efficacy of metformin for paediatric non-alcoholic steatohepatitis.
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[Clinical study on treatment of fatty liver by shennong ganzhining].
Lei, L, Ai, SM
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2005;(1):19-21
Abstract
OBJECTIVE To observe the therapeutic effect and safety of Shennong Ganzhining (SG) in treating fatty liver. METHODS One hundred and ninety patients with fatty liver were randomly divided into two groups. The 142 patients in the treated group received SG and the 48 in the control group received Zhibituo treatment for 3 months. The comprehensive therapeutic effect after treatment, symptoms, signs, liver function, blood lipids and blood viscosity, as well as iconographic parameters were observed. RESULTS The total effective rate in the treated group was 80.98%, which was higher than that in the control group (75.00%), showing significant difference statistically (P < 0.05). Satisfactory effect was obtained in recovery of liver function, improvement of blood lipids, blood viscosity and iconographic parameters, no severe adverse reaction occurred. CONCLUSION SG is obviously effective in treating fatty liver with favorable safety.
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Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes.
Petersen, KF, Dufour, S, Befroy, D, Lehrke, M, Hendler, RE, Shulman, GI
Diabetes. 2005;(3):603-8
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To examine the mechanism by which moderate weight reduction improves basal and insulin-stimulated rates of glucose metabolism in patients with type 2 diabetes, we used (1)H magnetic resonance spectroscopy to assess intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) content in conjunction with hyperinsulinemic-euglycemic clamps using [6,6-(2)H(2)]glucose to assess rates of glucose production and insulin-stimulated peripheral glucose uptake. Eight obese patients with type 2 diabetes were studied before and after weight stabilization on a moderately hypocaloric very-low-fat diet (3%). The diabetic patients were markedly insulin resistant in both liver and muscle compared with the lean control subjects. These changes were associated with marked increases in IHL (12.2 +/- 3.4 vs. 0.6 +/- 0.1%; P = 0.02) and IMCL (2.0 +/- 0.3 vs. 1.2 +/- 0.1%; P = 0.02) compared with the control subjects. A weight loss of only approximately 8 kg resulted in normalization of fasting plasma glucose concentrations (8.8 +/- 0.5 vs. 6.4 +/- 0.3 mmol/l; P < 0.0005), rates of basal glucose production (193 +/- 7 vs. 153 +/- 10 mg/min; P < 0.0005), and the percentage suppression of hepatic glucose production during the clamp (29 +/- 22 vs. 99 +/- 3%; P = 0.003). These improvements in basal and insulin-stimulated hepatic glucose metabolism were associated with an 81 +/- 4% reduction in IHL (P = 0.0009) but no significant change in insulin-stimulated peripheral glucose uptake or IMCL (2.0 +/- 0.3 vs. 1.9 +/- 0.3%; P = 0.21). In conclusion, these data support the hypothesis that moderate weight loss normalizes fasting hyperglycemia in patients with poorly controlled type 2 diabetes by mobilizing a relatively small pool of IHL, which reverses hepatic insulin resistance and normalizes rates of basal glucose production, independent of any changes in insulin-stimulated peripheral glucose metabolism.
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Relation between liver fat content and the rate of VLDL apolipoprotein B-100 synthesis in children with protein-energy malnutrition.
Badaloo, A, Reid, M, Soares, D, Forrester, T, Jahoor, F
The American journal of clinical nutrition. 2005;(5):1126-32
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BACKGROUND Fatty infiltration of the liver is associated with an increased morbidity and mortality in children with severe protein-energy malnutrition (PEM), but its pathogenesis remains unclear. Although impaired synthesis of VLDL apolipoprotein B-100 (VLDL-apo B-100) is generally accepted as the pathogenetic mechanism, the rate of it synthesis has not been measured in children with PEM. OBJECTIVE The objective of the study was to ascertain the relation between the degree of hepatic steatosis and the rate of VLDL-apo B-100 synthesis in children with PEM. DESIGN The fractional and absolute rates of VLDL-apo B-100 synthesis were measured with a prime-constant intravenous infusion of [2H3]leucine in 13 severely malnourished children (8 boys and 5 girls) aged 7-18 mo. Hepatic fat content was estimated by computerized tomography scanning by using the ratio of liver to spleen (L:S) attenuation. The ratio is inversely related to hepatic fat content such that the lower the L:S, the greater the amount of fat in the liver. RESULTS There were significant inverse relations between L:S attenuation and VLDL-apo B-100 concentration (P < 0.02), the absolute rate of VLDL-apo B-100 synthesis (P < 0.02), and plasma triacylglycerol (P < 0.02) and serum cholesterol (P < 0.05) concentrations. CONCLUSIONS These results suggest that children with PEM synthesize VLDL-apo B-100 at a faster rate as the degree of hepatic fat infiltration increases. Thus, fatty infiltration of the liver in PEM is not due to a reduction in the synthesis of VLDL-apo B-100.
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A pilot study of orlistat treatment in obese, non-alcoholic steatohepatitis patients.
Harrison, SA, Fincke, C, Helinski, D, Torgerson, S, Hayashi, P
Alimentary pharmacology & therapeutics. 2004;(6):623-8
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BACKGROUND Treatment options for non-alcoholic steatohepatitis (NASH) are limited. Weight loss remains the most recommended therapy. Orlistat is an effective adjunct to dietary weight loss therapy. AIM: To evaluate the efficacy of orlistat, given for 6 months to patients with obesity and biopsy confirmed NASH. METHODS Ten obese patients with biopsy proven NASH were enrolled. Orlistat was given with meals for 6 months. Body Mass Index (BMI), liver enzymes, haemoglobin A1c, fasting lipids and glucose were assessed at baseline and at completion of the study. Paired liver histology was obtained. RESULTS Six women and four men were enrolled. The mean weight loss was 22.7 lb and ranged from 0 to 24.3%. The following clinical values significantly improved: mean BMI: 43.4-39.8 (P = 0.007); mean haemoglobin A1c (%): 7.14-5.95 (P = 0.021); mean alanine aminotransferase (ALT) (U/L): 93 -54 (P = 0.009); and mean aspartate aminotransferase (AST) (U/L): 79-48 (P = 0.008). Steatosis improved in six patients, and fibrosis improved in three patients. CONCLUSIONS Orlistat therapy and dietary counselling were associated with significant decreases in body weight, haemoglobin A1c, ALT and AST. A 10% or greater reduction in weight improved steatosis and fibrosis as well as haemoglobin A1c levels in the majority of patients treated for 6 months. Controlled trials of longer duration are warranted to assess for histopathologic improvement as well as cost-efficacy in comparison to diet and exercise alone.