Despite the increasing prevalence of nonalcoholic fatty liver disease (NAFLD), its pathogenesis and clinical significance remain poorly defined. In this study, we examined and compared the distribution of hepatic triglyceride content (HTGC) in 2,287 subjects from a multiethnic, population-based sample (32.1% white, 48.3% black, and 17.5% Hispanic) using proton magnetic resonance spectroscopy. HTGC varied over a wide range (0.0%-41.7%; median, 3.6%) in the population. Almost one third of the population had hepatic steatosis, and most subjects with hepatic steatosis had normal levels of serum alanine aminotransferase (79%). The frequency of hepatic steatosis varied significantly with ethnicity (45% in Hispanics; 33% in whites; 24% in blacks) and sex (42% in white men; 24% in white women). The higher prevalence of hepatic steatosis in Hispanics was due to the higher prevalence of obesity and insulin resistance in this ethnic group. However, the lower frequency of hepatic steatosis in blacks was not explained by ethnic differences in body mass index, insulin resistance, ethanol ingestion, or medication use. The prevalence of hepatic steatosis was greater in men than women among whites, but not in blacks or Hispanics. The ethnic differences in the frequency of hepatic steatosis in this study mirror those observed previously for NAFLD-related cirrhosis (Hispanics > whites > blacks). In conclusion, the significant ethnic and sex differences in the prevalence of hepatic steatosis documented in this study may have a profound impact on susceptibility to steatosis-related liver disease. (HEPATOLOGY 2004;40:1387-1395

Despite the increasing prevalence of nonalcoholic fatty liver disease (NAFLD), the criteria used to diagnose the disorder remain poorly defined. Localized proton magnetic resonance spectroscopy (MRS) accurately measures hepatic triglyceride content (HTGC) but has been used only in small research studies. Here, MRS was used to analyze the distribution of HTGC in 2,349 participants from the Dallas Heart Study (DHS). The reproducibility of the procedure was validated by showing that duplicate HTGC measurements were high correlated (r = 0.99, P < 0.001) and that the coefficient of variation between measurements was low (8.5%). Intake of a high-fat meal did not significantly affect the measurements, and values were similar when measurements were made from the right and left hepatic lobes. To determine the "upper limit of normal" for HTGC, the distribution of HTGC was examined in the 345 subjects from the DHS who had no identifiable risk factors for hepatic steatosis (nonobese, nondiabetic subjects with minimal alcohol consumption, normal liver function tests, and no known liver disease). The 95th percentile of HTGC in these subjects was 5.56%, which corresponds to a hepatic triglyceride level of 55.6 mg/g. With this value as a cutoff, the prevalence of hepatic steatosis in Dallas County was estimated to be 33.6%. Thus MRS provides a sensitive, quantitative, noninvasive method to measure HTGC and, when applied to a large urban US population, revealed a strikingly high prevalence of hepatic steatosis.

We validate the use of 1H magnetic resonance spectroscopy (MRS) to quantitatively differentiate between adipocyte and intracellular triglyceride (TG) stores by monitoring the TG methylene proton signals at 1.6 and 1.4 ppm, respectively. In two animal models of intracellular TG accumulation, intrahepatic and intramyocellular TG accumulation was confirmed histologically. Consistent with the histological changes, the methylene signal intensity at 1.4 ppm increased in both liver and muscle, whereas the signal at 1.6 ppm was unchanged. In response to induced fat accumulation, the TG concentration in liver derived from 1H MRS increased from 0 to 44.9 ± 13.2 μmol/g, and this was matched by increases measured biochemically (2.1 ± 1.1 to 46.1 ± 10.9 μmol/g). Supportive evidence that the methylene signal at 1.6 ppm in muscle is derived from investing interfascial adipose tissue was the finding that, in four subjects with generalized lipodystrophy, a disease characterized by absence of interfacial fat, no signal was detected at 1.6 ppm; however, a strong signal was seen at 1.4 ppm. An identical methylene chemical shift at 1.4 ppm was obtained in human subjects with fatty liver where the fat is located exclusively within hepatocytes. In experimental animals, there was a close correlation between hepatic TG content measured in vivo by 1H MRS and chemically by liver biopsy [ R = 0.934; P < .0001; slope 0.98, confidence interval (CI) 0.70–1.17; y-intercept 0.26, CI −0.28 to 0.70]. When applied to human calf muscle, the coefficient of variation of the technique in measuring intramyocellular TG content was 11.8% in nonobese subjects and 7.9% in obese subjects and of extramyocellular (adipocyte) fat was 22.6 and 52.5%, respectively. This study demonstrates for the first time that noninvasive in vivo 1H MRS measurement of intracellular TG, including that within myocytes, is feasible at 1.5-T field strengths and is comparable in accuracy to biochemical measurement. In addition, in mixed tissue such as muscle, the method is clearly advantageous in differentiating between TG from contaminating adipose tissue compared with intramyocellular lipids.

Non-esterified fatty acids (NEFA) serve as an important energy source for most body tissues, particularly during periods of food deprivation, but recent evidence suggests that these same molecules subserve a much broader function in whole body fuel homeostasis by virtue of their ability to act as potent signalling entities in a variety of cellular processes. One such auxiliary role of NEFA is to heighten the responsiveness of the pancreatic beta cell to a variety of insulin secretagogues. Importantly, this fatty acid-beta cell interaction, though designed by nature for physiological purposes, can, under certain circumstances, take on a pathophysiological dimension. Some new developments surrounding this Jekyll and Hyde character of fatty acids will be reviewed briefly below.NEFA and normal beta-cell function (i) The case for glucose-fatty acid cross-talk in the control of insulin secretion It is generally agreed that in order to stimulate insulin secretion, glucose must first enter the beta cell via a glucose transporter and then be metabolized to a point beyond pyruvate in a process initiated by the high K m enzyme, glucokinase. This in turn is thought to cause an increase in the ATP:ADP ratio, closure of the cell surface K + ATP channels, cell depolarization and opening of the voltage-sensitive Ca 2 channels, leading to a rise in intracellular Ca 2+ [Ca 2+ ] i and activation of exocytosis [1]. Additional mechanisms contribute, however, to the regulation of insulin secretion in the whole animal setting [2]. One of these, referred to as the K + ATP channel-independent pathway, augments the response to a raised [Ca 2+ ] i generated through the more classical pathway. A second, referred to as the K + ATP channel-independent, Ca 2+ -independent pathway of glucose signalling, appears to involve a GTP-dependent step that is activated through the combined effects of protein kinase A (PKA) and protein kinase C (PKC).Although details of these partially overlapping signalling systems remain to be worked out, yet another element must now be brought into the discussion. This has to do with the powerful influence of glucose metabolism on the intracellular disposition of fatty acids and the potential role of this interaction in stimulus-secretion coupling. That fatty acids can considerably enhance glucose-stimulated insulin secretion (GSIS) in intact animals and humans was recognized in early studies from a number of laboratories [3±10] but since many interventions that modulate NEFA concentrations also alter glucose uptake [11], it was often felt that changes in insulin sensitivity could explain most of the fluctuations in plasma insulin concentrations. Recent studies specifically designed to monitor insulin secretion patterns following manipulation of the plasma NEFA concentration have, however, generated renewed interest in the importance of these substrates in governing beta-cell function [12, 13; see below].Efforts to elucidate how fatty acids influence betacell function have led to a series of important findi...

Recent experimental data suggest that adiposity directly damages the heart by promoting ectopic deposition of triglyceride, a process known as myocardial steatosis. The goal of this study was to develop and validate proton magnetic resonance spectroscopy (