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Department of Medicine, Division of Diabetes (J.W., H.Y.-J.), Obesity Research Unit, and Departments of Psychiatry (K.L., A.R.) and Oncology (A.-M.H.), University of Helsinki, FIN-00029 Helsinki, Finland; and National Public Health Institute (I.S., A.A.), FIN-00300 Helsinki, Finland
Address all correspondence and requests for reprints to: Jukka Westerbacka, M.D., Ph.D., Department of Medicine, University of Helsinki, P.O. Box 340, FIN-00029 HUCH, Helsinki, Finland. E-mail: jukka.westerbacka{at}helsinki.fi.
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Abstract |
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Design and methods: 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.
Results: 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.
Conclusion: These data suggest that the amount of dietary fat influences liver fat content.
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Introduction |
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The increased triglyceride deposition in the liver could be a result of excessive influx of free fatty acids (FFA) from endogenous fat depots or to increased hepatic extraction of FFA. Regarding the possibility that liver fat could be derived from exogenous fat, early studies suggested that although remnants can be taken up directly by the liver, all FFA released via intravascular lipolysis from very-low-density lipoprotein (VLDL) and chylomicrons are immediately stored in either adipose tissue or skeletal muscle (12). However, recent human studies quantifying systemic release of lipoprotein lipase-generated fatty acids have shown that a significant proportion of FFA released from chylomicrons and VLDL fat are available for storage in tissues other than skeletal muscle and adipose tissue (13). In animals, the liver has been shown to have a high capacity to accumulate triglycerides, and the size of this pool can change severalfold within hours (14). Recent studies in humans have also shown that up to 20% of dietary fatty acids are secreted as VLDL triglycerides within 6 h after a meal (15). This suggests that a significant fraction of fatty acids are taken up by the liver during the postprandial period. We have previously found a correlation between the percent saturated and total fat in the diet and liver fat content (5). Diet intervention studies have suggested that insulin sensitivity is impaired in nondiabetic subjects on a diet containing a high proportion of saturated fat compared with monounsaturated (16) or polyunsaturated (17) fat. Even ingestion of a single meal with high saturated compared with n-6 or n-3 polyunsaturated or monounsaturated fatty acids has been shown to decrease insulin sensitivity (18). It is, however, unknown whether alterations in liver fat occur during isocaloric diet interventions. In the present study, we wished to determine in obese nondiabetic women whether a decrease in the percent fat, especially saturated fat, in the diet decreases liver fat content and serum insulin concentrations. In animals, the dietary fatty acid composition has been shown to influence liver fat independent of saturated or total fat (19). The fatty acid composition of serum phospholipids, which reflects medium-term (weeks to months) changes in dietary fatty acids (20), were measured to determine whether the diet intervention was associated with changes in fatty acid composition.
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Subjects and Methods |
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Ten overweight apparently healthy premenopausal women (age, 43 ± 5 yr; mean ± SD; body mass index, 33 ± 4 kg/m2; range, 27–38 kg/m2) were recruited based on the following inclusion criteria: 1) age 18–60 yr and 2) no known acute or chronic disease based on history and physical examination and standard laboratory tests (blood counts, serum creatinine, TSH, electrolyte concentrations, and electrocardiogram). Other exclusion criteria included treatment with drugs that may alter glucose tolerance, pregnancy, or clinical or biochemical evidence of any significant disease other than obesity. Elevated liver enzymes serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and 
-glutamyl transferase (GGT) was not an exclusion criterion, but patients with serological evidence of hepatitis B or C, autoimmune hepatitis, clinical signs or symptoms of inborn errors of metabolism, or a history of use of toxins or drugs associated with liver steatosis were excluded as were subjects consuming more than 20 g of alcohol per day. To maximize the power to detect potential effects of the diets on liver fat content, the recruited subjects had increased liver fat content verified using spectroscopy in previous metabolic studies. Each subject underwent a history and physical examination, and a blood sample was taken for screening purposes as detailed above. The nature and potential risks of the study were explained to all subjects before obtaining their written informed consent. The protocol was approved by the ethics committee of the Helsinki University Central Hospital.
The women were placed on two successive 2-wk isocaloric diets, which contained either 16 or 56% of energy from fat in randomized order using crossover design. Daily energy requirements for weight maintenance for each subject were determined by a dietitian (K.L.) by means of 3-d food records and knowledge of weight and height. The distribution of energy from fat, carbohydrate, and protein was 36 ± 7, 45 ± 9, and 19 ± 4% in the pre-study diet of the subjects. The isocaloric diets, calculated to yield either 15 or 60% of energy as fat, were designed by exchanging dietary fat for carbohydrate in a crossover fashion without changing total caloric intake. The food for diets was provided to the patients by the clinical research unit. The actual dietary intake was recorded by daily food records kept by the subjects for 14 d. The dietary records were analyzed using the NUTRICA software (version 3.0; Research Centre of the Social Insurance Institution, Helsinki, Finland). The distribution of energy from fat, carbohydrate, and protein was, respectively, 16 ± 1, 61 ± 3, and 19 ± 1% during the low-fat diet and 56 ± 1, 31 ± 1, and 13 ± 1% during the high-fat diet. Total caloric intake was similar during the low-fat (151 ± 9 kJ/fat-free mass·d) and high-fat (157 ± 6 kJ/fat-free mass·d) diet. The low-fat diet decreased the intake of both saturated (5 ± 1 vs. 28 ± 1%, low- vs. high-fat diet; P < 0.001) and monounsaturated (5 ± 1 vs. 16 ± 1%; P < 0.001) and polyunsaturated (3 ± 1 vs. 5 ± 1%; P < 0.001) fat. Alcohol intake averaged 1 ± 1% of total energy intake during both diets. Serum insulin, glucose, lipids, liver enzymes, and fatty acid composition of phospholipids were measured in a blood sample drawn after an overnight fast. Indirect calorimetry measurements were performed before and after the low- and high-fat diets after an overnight fast starting at 0800 h as detailed below.
Methods
Liver fat content. Localized single-voxel (2 x 2 x 2 cm3) proton spectra were acquired using a 1.5-T whole-body system (Siemens Magnetom Vision, Erlangen, Germany), which consisted of a combination of whole-body and loop surface coils for radiofrequency transmitting and signal receiving. T1-weighted high-resolution magnetic resonance images were used for localization of the voxel of interest within the right lobe of the liver. Vascular structures and the proximity of sc fat tissue were avoided in localization of the voxel. Subjects were lying on their stomach on the surface coil, which was embedded in a mattress to minimize abdominal movement caused by breathing. The single-voxel spectra were recorded by using the stimulated-echo acquisition mode sequence with an echo time of 20 msec, a repetition time of 3000 msec, a mixing time of 30 msec, and 1024 data points over 1000-kHz spectral width with 64 averages. Water-suppressed spectra with 128 averages were also recorded to detect weak lipid signals. The short echo time and the long repetition time were chosen to ensure a fully relaxed water signal, which was used as an internal standard. Chemical shifts were measured relative to water at 4.80 parts per million. The methylene signal, which represents intracellular triglyceride, was measured at 1.4 parts per million. Signal intensities were quantified by using analysis program VAPRO-MRUI (http://www.mrui.uab.es/mrui/). Spectroscopic intracellular triglyceride content (liver fat) was expressed as methylene/(water + methylene) signal area ratio x 100. This measurement has been validated against histologically determined lipid content (21) and against estimates of fatty degeneration or infiltration by x-ray computed assisted tomography (22). All spectra were analyzed by a physicist (A.-M.H.) who was unaware of any of the clinical data.
Intraabdominal and sc fat (magnetic resonance imaging). A series of T1-weighted transaxial scans for the determination of intraabdominal and sc fat were acquired from a region covering an 8-cm region immediately above the fourth and fifth lumbar interspace (eight slices; field of view, 375 x 500 mm2; slice thickness,10 mm; breath-hold repetition time,138.9 msec; echo time, 4.1 msec). Intraabdominal and sc fat areas were measured using an image analysis program (Alice 3.0; Parexel, Waltham, MA). A histogram of pixel intensity in the intraabdominal region was displayed, and the intensity corresponding to the nadir between the lean and fat peaks was used as a cutoff point. Intraabdominal adipose tissue was defined as the area of pixels in the intraabdominal region above this cutoff point. For calculation of sc adipose tissue area, a region of interest was first manually drawn at the demarcation of sc adipose tissue and intraabdominal adipose tissue as previously described (22).
Indirect calorimetry. Glucose and lipid oxidation rates were measured with indirect calorimetry using the Deltatrac Metabolic Monitor (Datex, Helsinki, Finland). Samples of inspired and expired air, which were suctioned at 40 liters/min, were analyzed for O2 and CO2 concentration differences using paramagnetic O2 and CO2 analyzers, respectively. The hood was placed on the subject’s head 10 min before the measurement was started. Urine was collected during the study, and the protein oxidation rate was estimated from urea nitrogen excretion (1 g nitrogen = 6.25 g protein). The following constants were used for calculation of glucose and lipid oxidation rates from gas exchange data: oxidation of 1 g protein requires 966 ml O2 and produces 782 ml CO2; 1 g glucose requires 746 ml O2 and produces 746 ml CO2; and 1 g lipid requires 2029 ml O2 and produces 1430 ml CO2 (23).
Other measurements
Blood samples were taken after an overnight fast for measurement of plasma glucose, serum insulin, hemoglobin A1C, liver enzymes, serum triglycerides, total and high-density lipoprotein (HDL) cholesterol concentrations. The percentage of body fat was determined by using bioelectrical impedance analysis (BioElectrical Impedance Analyzer System model BIA-101A; RJL Systems, Detroit, MI) (24). Waist circumference was measured midway between spina iliaca superior and the lower rib margin (25).
Analytical procedures.
Plasma glucose concentrations were measured in duplicate with the glucose oxidase method using a Beckman Glucose Analyzer II (Beckman Instruments, Fullerton, CA) (26). Serum free insulin concentrations were measured using the Auto-DELFIA kit from Wallac (Turku, Finland). Hemoglobin A1C was measured by HPLC with the fully automated Glycosylated Hemoglobin Analyzer System (Bio-Rad, Richmond, CA) (27). Serum total cholesterol, HDL cholesterol, and triglyceride concentrations were measured with respective enzymatic kits from Roche Diagnostics using an autoanalyzer (Roche Diagnostics Hitachi 917; Hitachi Ltd., Tokyo, Japan). LDL cholesterol concentration was calculated using the formula of Friedewald et al. (28). Serum ALT, AST, and GGT activities were determined as recommended by the European Committee for Clinical Laboratory Standards. Serum adiponectin concentrations were measured using the ELISA kit from B-Bridge International (San Jose, CA).
Serum FFA and fatty acid composition of serum phospholipids
Serum FFA were measured using a fluorometric method (29). The fatty acid methyl ester composition of serum phospholipids was determined with gas chromatography after a thin-layer chromatography separation of phospholipids from serum fat extract (30) and interesterification to methyl esters (31). The gas chromatograph HP 6980 (Hewlett-Packard, Avondale, PA) was equipped with a 25-m silica column NB 351 (HNU-Nordion Ltd., Helsinki, Finland) and a split injection system. Hydrogen was used as carrier gas. The interassay precision varied from 1–8%, depending on the peak size.
Statistical analyses
Changes by low- and high-fat diets were analyzed using Wilcoxon matched-pair test. Period effect was analyzed as a period x treatment effect using repeated-measures ANOVA after log-transformation of nonnormally distributed variables. Correlation analyses were performed using Spearman’s nonparametric correlations coefficient. Calculations were made using GraphPad Prism version 3.00 for Windows (GraphPad Software, San Diego, CA) and SPSS 11.0 for Windows (SPSS Inc., Chicago, IL). Data are shown as mean ± SD. A P value less than 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Liver fat averaged 10 ± 7% at baseline. 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) (Fig. 1). Liver fat before low- and high-fat diets was similar (10 ± 8 vs. 10 ± 8% before low- vs. high-fat diet). In repeated-measures two-way ANOVA, the time x diet interaction term was significant (P = 0.019), whereas the time x order of diet terms or change in weight were not.
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). There were no significant changes in fasting plasma glucose, serum FFA, LDL and HDL cholesterol, triglycerides, adiponectin, or liver enzymes (Table 1). Rates of total energy expenditure did not change during the low-fat (0.051 ± 0.003 vs. 0.052 ± 0.004 J/kg·min, before vs. after) or high-fat (0.053 ± 0.004 vs. 0.052 ± 0.005 J/kg·min, respectively) diet. Similarly, rates of lipid, carbohydrate, or protein oxidation remained unchanged (data not shown).
Changes in the percent fatty acid composition of serum phospholipids are shown in Table 2. The proportion of the most abundant saturated fatty acid, palmitic acid, increased significantly during the low-fat diet and decreased significantly during the high-fat diet. The most abundant essential polyunsaturated fatty acid, linoleic acid, tended to decrease during the low- and increase during the high-fat diet (P < 0.1). Docosahexaenoic acid increased during the low-fat and decreased during the high-fat diet. The proportions of saturated, monounsaturated, and polyunsaturated n-6 and n-3 fatty acids remained unchanged.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The dietary intervention in the present study was designed to mimic real life and not to distinguish between effects of changes in composition of fat. In this study, the high-fat diet contained 3.6 times more fat than the low-fat diet. The difference in fat intake was mainly a result of the difference in the intake of calories from saturated but also from mono- and polyunsaturated fat. This did not result in significant changes in total serum FFA, although minor changes were seen in fatty acid composition of serum phospholipids, which are considered to reflect medium-term (weeks to months) changes in dietary fat intake (20, 32, 33). In the present study, the proportion of palmitic acid increased and stearic acid decreased during the low-fat diet. These changes resemble those observed during inhibition of fat absorption with the intestinal lipase inhibitor orlistat, during which the proportion of serum palmitic increases and stearic acid decreases (34). An increase in the proportion of palmitic acid in phospholipids was also found during a 28-d, low- compared with high-fat diet in 10 normal subjects (35). Palmitic acid is a primary product of fatty acid synthase and the initial product of de novo lipogenesis, and therefore the increase in palmitic acid during lowering of exogenous intake most likely reflects accelerated synthesis of endogenous fatty acids (36). Regarding effects of changes in other fatty acids on liver fat, in mice, a diet supplemented with t10,c12-conjugated linoleic acid for 8 wk increases liver fat 4-fold (37). Fish oil, which is rich in n-3 fatty acids, has been reported to decrease liver triglyceride content in rats when compared with control or safflower oil-fed rats (19). In the present study, t10,c12-conjugated linoleic acid isomer that is not a normal dietary constituent was not identified separately.
Multiple studies have documented that a high-fat diet rapidly induces hepatic steatosis in mice (38), rats (39, 40, 41), rabbits (14), and dogs (42, 43). For example, normal rats develop fasting hyperinsulinemia, steatosis, abnormal mitochondria and mononuclear inflammation, and increased TNF
, collagen type 1, and 1(I) procollagen expression in the liver when fed a high-fat (71%) diet for 3 wk compared with feeding a diet containing 35% fat (41). Regarding the origin of fatty acids in hepatocellular triglycerides, the current dogma states that except for the small amount of remnants that are taken up by the liver directly, all FFA released via intravascular lipolysis from VLDL and chylomicrons are stored in either adipose tissue or skeletal muscle before they can be transported elsewhere (12). There are, however, some old animal and recent human data that would suggest that this is not necessarily true. In rats given alcohol with fat-containing diets (43% of calories), fatty acids accumulating in liver triglycerides have a large component of dietary fatty acids (40). In humans, up to 20% of dietary fatty acids are secreted as VLDL triglycerides within 6 h after a meal, implying that a significant fraction of fatty acids are taken up by the liver during the postprandial period (15). In another study, one third of triglycerides were found to be released into the systemic circulation after a fatty meal containing radiolabeled triglycerides (44). Acute studies using an iv infusion of lipid have also shown that 36% of lipoprotein lipase-generated FFA are released into the circulation and are thereby available for uptake by other tissues in healthy men (13). The present data support these observations and also suggest, given that sc and intraabdominal fat volumes remained unchanged, that the liver may indeed be the first organ to store excessive amounts of fatty acids. This finding closely resembles that found recently in rats in which short-term fat feeding increased liver triglyceride and total fatty acyl-CoA 3-fold and induced hepatic but not muscle insulin resistance (39). As in the present study, there were no changes in visceral fat mass or body weight. The liver may also be able to rapidly mobilize its fat because we recently found that moderate weight loss reducing total fat mass by 14% reduced liver fat by 39% (34). Several previous studies have also shown beneficial effects of weight loss using gastric bypass or gastroplasty on liver fat in morbidly obese subjects and patients with nonalcoholic steatohepatitis (45).
The dietary interventions did not change rates of lipid, protein, or carbohydrate oxidation when measured after an overnight fast. The concentration of serum FFA also remained unchanged. These data are consistent with those of Bisschop et al. (46) who found no change in rates of substrate oxidation or FFA production or fat oxidation in response to feeding healthy volunteers diets containing either 0 or 41% fat for 7 d and with recent data in which short-term fat feeding in rats resulted in hepatic fat accumulation without changing fasting FFA concentrations, body weight, or fat distribution outside the liver (39). Although FFA kinetics were not measured in the present study and liver fat was not measured in the study of Bisschop et al. (46), together these data would support the hypothesis that alterations in flux of FFA under fasting conditions did not contribute to changes in liver fat content. We also did not observe any change in serum triglycerides, although high-carbohydrate/low-fat diets have in many studies increased serum triglyceride concentrations in normolipidemic and slightly hypertriglyceridemic subjects (47) and decreased them in those with more marked hypertriglyceridemia (48). Approximately half of the present study subjects were mildly hypertriglyceridemic. The lack of a hypertriglyceridemic effect of the high-fat/low-carbohydrate diet is unclear but might have been a result of the short duration of the diet and small sample size. Regardless, the data suggest that changes in liver fat and serum fasting insulin can be observed in the absence of changes in serum triglycerides. The change in insulin that accompanied those in liver fat is in keeping with several recent studies showing a causal relationship between liver fat and insulin in lipoatrophic animal models (49) and close correlations between the two parameters in cross-sectional and intervention studies in humans (5, 6, 10, 50, 51, 52, 53).
To conclude, the present data suggest that large differences in diet composition influence liver fat content and fasting insulin concentrations in humans. Thus, the large interindividual variation in liver fat content independent of obesity could at least in part be a result of differences in dietary intake. The importance of fatty acid composition of diet remains to be studied. Changes in serum adiponectin or fasting FFA do not seem to be involved in mediating the changes.
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Acknowledgments |
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Footnotes |
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First Published Online March 1, 2005
Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; FFA, free fatty acids; GGT, -glutamyl transferase; HDL, high-density lipoprotein; VLDL, very-low-density lipoprotein.
Received October 11, 2004.
Accepted February 17, 2005.
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