Abstract
Fatty liver is frequent in the apolipoprotein B (apoB)-defective genetic form of familial hypobetalipoproteinemia (FHBL), but interindividual variability in liver fat is large. To explain this, we assessed the roles of metabolic factors in 32 affected family members with apoB-defective FHBL and 33 related and unrelated normolipidemic controls matched for age, sex, and indices of adiposity. Two hour, 75 g oral glucose tests, with measurements of plasma glucose and insulin levels, body mass index, and waist-hip ratios were obtained. Abdominal subcutaneous, intraperitoneal (IPAT), and retroperitoneal adipose tissue masses were quantified by MR imaging, and hepatic fat was quantified by MR spectroscopy. Mean +/- SD liver fat percentage values of FHBL and controls were 14.8 +/- 12.0 and 5.2 +/- 5.9, respectively (P = 0.001). Means for these measures of obesity and insulin action were similar in the two groups. Important determinants of liver fat percentage were FHBL-affected status, IPAT, and area under the curve (AUC) insulin in both groups, but the strongest predictors were IPAT in FHBL (partial R(2) = 0.55, P < 0.0002) and AUC insulin in controls (partial R(2) = 0.59, P = 0.0001). Regression of liver fat percentage on IPAT fat was significantly greater for FHBL than for controls (P < 0.001). In summary, because apoB-defective FHBL imparts heightened susceptibility to liver triglyceride accumulation, increasing IPAT and insulin resistance exert greater liver fat-increasing effects in FHBL.
Highlights
Fatty liver is frequent in the apolipoprotein B-defective genetic form of familial hypobetalipoproteinemia (FHBL), but interindividual variability in liver fat is large
Three genetic subclasses of FHBL have been identified to date: 1) mutations of the apolipoprotein B (apoB) gene (APOB) that lead to dysfunctional export of hepatic triglycerides via the VLDL export system and to fatty liver in humans [25,26,27,28] and mouse models [29, 30]; 2) FHBL linked to a susceptibility locus on chromosome 3p21 [31, 32]; and 3) FHBL linked to neither of the above
We have reported that the mean liver triglyceride content in apoB-impaired FHBL subjects is ف5-fold that of controls [33], but liver fat content in FHBL subjects varies greatly among individuals
Summary
Fatty liver is frequent in the apolipoprotein B (apoB)-defective genetic form of familial hypobetalipoproteinemia (FHBL), but interindividual variability in liver fat is large. Several mouse models have been engineered that result in fatty liver: mouse overexpressors of genes specifying enzymes or transcription factors of the fatty acid synthetic pathway [12], knockouts of genes of the hepatic fatty acid oxidation pathways [13], and genes that regulate the development of adipose tissue [14] Some of these mice exhibit aspects of the metabolic syndrome, such as insulin resistance. In seeking sources of variation, we determined indices of adiposity such as the waist-hip ratio and the body mass index (BMI) and indices of insulin action such as area under the curve (AUC) for glucose and insulin during oral glucose tolerance tests in both FHBL and control subjects Mean values for these parameters did not differ in the two groups, suggesting that higher levels of liver fat in FHBL subjects were not attributable to more adiposity or insulin resistance in FHBL subjects. This suggests that FHBL subjects are more susceptible to developing fatty livers at any given amount of abdominal adipose tissue than are controls
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