Changes In Liver Fat Research Articles

The DGAT2 gene is a candidate for the dissociation between fatty liver and insulin resistance in humans

The enzyme DGAT (acyl-CoA:diacylglycerol acyltransferase) catalyses the final step of triacylglycerol (triglyceride) synthesis. Mice overexpressing hepatic DGAT2 fed a high-fat diet develop fatty liver, but not insulin resistance, suggesting that DGAT2 induces a dissociation between fatty liver and insulin resistance. In the present study, we investigated whether such a phenotype also exists in humans. For this purpose, we determined the relationships between genetic variability in the DGAT2 gene with changes in liver fat and insulin sensitivity in 187 extensively phenotyped subjects during a lifestyle intervention programme with diet modification and an increase in physical activity. Changes in body fat composition [MR (magnetic resonance) tomography], liver fat and intramyocellular fat ((1)H-MR spectroscopy) and insulin sensitivity [OGTT (oral glucose tolerance test) and euglycaemic-hyperinsulinaemic clamp] were determined after 9 months of intervention. A change in insulin sensitivity correlated inversely with changes in total body fat, visceral fat, intramyocellular fat and liver fat (OGTT, all P<0.05; clamp, all P< or =0.03). Changes in total body fat, visceral fat and intramyocellular fat were not different between the genotypes of the SNPs (single nucleotide polymorphisms) rs10899116 C>T and rs1944438 C>T (all P> or =0.39) of the DGAT2 gene. However, individuals carrying two or one copies of the minor T allele of SNP rs1944438 had a smaller decrease in liver fat (-17+/-10 and -24+/-5%; values are means+/-S.E.M.) compared with subjects homozygous for the C allele (-39+/-7%; P=0.008). In contrast, changes in insulin sensitivity were not different among the genotypes (OGTT, P=0.76; clamp, P=0.53). In conclusion, our findings suggest that DGAT2 mediates the dissociation between fatty liver and insulin resistance in humans. This finding may be important in the prevention and treatment of insulin resistance and Type 2 diabetes in subjects with fatty liver.

High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease

Objective:Lifestyle intervention with diet modification and increase in physical activity is effective for reducing hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD). However, for a similar weight loss,...

Rosiglitazone Reduces Liver Fat and Insulin Requirements and Improves Hepatic Insulin Sensitivity and Glycemic Control in Patients with Type 2 Diabetes Requiring High Insulin Doses

Liver fat is an important determinant of insulin requirements during insulin therapy. Peroxisome proliferator-activated receptor (PPAR)-gamma agonists reduce liver fat. We therefore hypothesized that type 2 diabetic patients using exceptionally high doses of insulin might respond well to addition of a PPARgamma agonist. We determined the effect of the PPARgamma agonist rosiglitazone on liver fat and directly measured hepatic insulin sensitivity in 14 patients with type 2 diabetes (aged 51 +/- 3 yr, body mass index 36.7 +/- 1.1 kg/m2), who were poorly controlled (glycosylated hemoglobin A 1c (HbA 1c) 8.9 +/- 0.4%) despite using high doses of insulin (218 +/- 22 IU/d) in combination with metformin. Liver fat content (1H-magnetic resonance spectroscopy), hepatic insulin sensitivity [6 h hyperinsulinemic euglycemic clamp (insulin 0.3 mU/kg.min) combined with [3-3H]glucose], body composition (magnetic resonance imaging), substrate oxidation rates (indirect calorimetry), clinical parameters, and liver enzymes were measured before and after rosiglitazone treatment (8 mg/d) for 8 months. During rosiglitazone, HbA(1c) decreased from 8.9 +/- 0.4% to 7.8 +/- 0.3% (P = 0.007) and insulin requirements from 218 +/- 22 to 129 +/- 20 IU/d (P = 0.002). Liver fat content decreased by 46 +/- 9% from 20 +/- 3% to 11 +/- 3% (P = 0.0002). Hepatic insulin sensitivity, measured from the percent suppression of endogenous glucose production by insulin, increased from -40 +/- 7% to -89 +/- 12% (P = 0.001). The percent change in liver fat correlated with the percent decrease in HbA 1c (r = 0.53, P = 0.06), insulin dose (r = 0.66, P = 0.014), and suppression of endogenous glucose production (r = 0.76, P = 0.003). Our results suggest that rosiglitazone may be particularly effective in type 2 diabetic patients who are poorly controlled despite using high insulin doses. The mechanism is likely to involve reduced liver fat and enhanced hepatic insulin sensitivity.

Rapid significant weight loss and regional lipid deposition: Implications for insulin sensitivity

To compare regional lipid deposition and insulin sensitivity after differing weight loss strategies: very low calorie diet (VLCD) and laparoscopic adjustable gastric banding (LAGB). Thirty-nine obese women underwent anthropometry, proton magnetic resonance (MR) spectroscopy for assessment of liver fat (LFAT) and MR imaging for visceral (VAT) and subcutaneous abdominal fat volume (SAT) determination. Fasting blood was taken for insulin, glucose and free fatty acid (FFA) analysis. Measurements were repeated after 6-weeks Optifast VLCD (n = 14) or 3 months after LAGB (n = 25). Similar, significant (p < 0.001) weight loss occurred after VLCD (8%) and LAGB (9%). Both interventions induced significant (p < 0.001) and similar reductions in body mass index (BMI) and waist circumference, and in SAT and VAT (VLCD p < 0.05, LAGB p < 0.001). LFAT fell only after VLCD (p < 0.05). Plasma FFA only fell after LAGB (p < 0.05). Homeostasis model assessment (HOMA-R) improved only following VLCD (p < 0.05). No relations were detected between the changes in LFAT, VAT and SAT. The change in LFAT related to the change in HOMA-R in both interventions combined (r = 0.410, p = 0.013) and in the VLCD group (r = 0.660, p = 0.020). There was no change in relative dietary fat intake after LAGB (p = 0.11). Caloric and fat restriction for 6 weeks (VLCD) reduces weight, SAT, VAT, LFAT and HOMA-R. Less severe caloric restriction for 12 weeks (LAGB) causes significant loss of weight, VAT and SAT but no detectable change in LFAT and HOMA-R. Following weight loss, a change in LFAT is related more to changes in insulin sensitivity or dietary fat than to abdominal adiposity loss.

Dietary Fat Content Modifies Liver Fat in Overweight Nondiabetic Subjects

Fat accumulation in the liver has been shown to be closely correlated with hepatic insulin resistance and features of insulin resistance, even independent of body weight. The reason for interindividual variation in liver fat content is unknown. Cross-sectional data suggest that dietary fat content may influence liver fat, but this possibility has not been directly tested in humans. Liver fat (proton spectroscopy), intraabdominal and sc fat (magnetic resonance imaging), and markers of insulin sensitivity (insulin, free fatty acids, and lipids) were determined in 10 normal, obese women (age, 43 +/- 5 yr, mean +/- sd; body mass index, 33 +/- 4 kg/m2; range, 27-38 kg/m2) at baseline and after two 2-wk isocaloric periods containing either 16% (low-fat diet) or 56% (high-fat diet) of total energy as fat. Liver fat at baseline averaged 10 +/- 7%. It decreased by 20 +/- 9% during the low-fat diet and increased by 35 +/- 21% during the high-fat diet (P = 0.014 for liver fat after low- vs. high-fat diets; P = 0.042 for change in liver fat by the low- vs. high-fat diet). Fasting serum insulin averaged 70 +/- 41 pmol/liter at baseline. It decreased to 60 +/- 24 pmol/liter during the low-fat diet (P = 0.007 vs. before low-fat diet) and increased to 81 +/- 44 pmol/liter during the high-fat diet (P = 0.040 vs. before high-fat diet; P = 0.005 for change in serum insulin during low- vs. high-fat diet). Serum lipids, free fatty acids, and intraabdominal and sc fat masses were unchanged. These data suggest that the amount of dietary fat influences liver fat content.

Pantothenic Acid Deficiency in Pregnant and Non-pregnant Guinea Pigs, with Special Reference to Effects on the Fetus

To study the effects of pantothenic acid deficiency during pregnancy in the guinea pig, it was necessary first to establish the appropriate duration of the deficiency period, by subjecting adult animals to the deficient diet. These experiments showed that the adult guinea pig is sensitive to a deficiency of pantothenic acid. Thirteen non-pregnant adults died within 10 to 41 days after institution of the deficient diet, and 3 pregnant animals survived only 9 to 16 days. Liver pantothenic acid and coenzyme A levels were markedly reduced, and liver fat concentration was greatly increased. Pair-feeding experiments showed that this increase in liver fat was at least partially due to decreased food intake. A transitory dietary deficiency of pantothenic acid during the ninth or tenth weeks of gestation (total period 70 days) resulted in loss of fetuses through abortion, or death of the mother. Deficiency during the tenth week appeared to produce a significant increase in the liver fat of the newborn. Concomitantly, liver pantothenic acid level was lower than normal, both at birth and at 7 days of age. Young whose mothers had received the deficient diet during the ninth, the seventh or the sixth weeks showed no significant changes in liver fat at birth, but liver pantothenic acid concentration was lower than normal. No gross morphological abnormalities were noted. Liver fat concentration in normal newborn guinea pigs was found to be more than 10 times the normal adult level. At 62 days of gestation, it was even higher than at birth, but it decreased after parturition to one-third of the newborn level by 2 days of age. In contrast, liver cholesterol showed only slight changes in the neonatal period. The experiments suggest that the greatest need for pantothenic acid during fetal development of the guinea pig is in the period shortly before birth.

Effect of aureomycin on liver fat and liver function.

Recent observations- indicate that some patients given aureomycin or terramycin developed fatty liver. This was associated with an increase in bromsulphthalein retention in some cases. The following experiments represent attempts to study this phenomenon. Methods. Aureomycin was administered to mongrel dogs Sprague—Dawley rats and humans in the manner and dose indicated in Table I. Serial data from dogs and humans fed aureomycin were compared to pre—treat—ment data. Rats fed or injected aureomycin were compared with pair—fed or pair—injected (saline) animals. Rats and dogs were continued on commercial rations and humans on their usual diet. Histological studies including fat stains were made of liver tissue from needle biopsies of dogs and necropsies from rats. Liver fat in rats was also determined chemically. The following liver function tests were performed on dogs and humans at weekly intervals: bromsulphthalein retention, serum bilirubin, thymol turbidity and zinc sulfate turbidity. In addition, cephalin cholesterol flocculation and gamma globulin turbidity tests were done on humas. LResults. (Table I). There were no significant changes in liver fat of dogs or rats as measured histologically and/or chemically afiter aureomycin administration for as long as 70 days. Two g aureomycin taken orally by three healthy young men for 310 days produced no changes in liver function tests in 2 subjects. One individual showed a change in bromsulphthalein retention from control values of 2% to 6% during therapy. This was not considered significant. There wereno changes in the other tests done in this subject. Comment. Dowling, et al. observed increased liver fat and even death in some animals treated with large amounts of aureomycin. Gyorgy, et al., has demonstrated that aureomycin actually prevents fatty liver and prolongs the survival of rats fed diets low in choline or methionine.

Effect of Choline on Atherosclerosis in the Rabbit Aorta.

SummaryFatty livers, with some increase in liver cholesterol, were produced by feeding rabbits a diet containing 0.43% cholesterol; 0.22% cholesterol produced no changes in liver fat. Both levels of cholesterol produced marked atheromatous lesions, and a striking increase in the cholesterol content of the aorta and blood. Three hundred mg of choline hydrochloride daily failed to counter-act the effect of cholesterol in the blood, liver or aorta.