Relationships between hepatic stearoyl-CoA desaturase-1 activity and mRNA expression with liver fat content in humans.

Stearoyl-CoA desaturase-1 (SCD1) has gained much interest as a future drug target to treat fatty liver and its consequences. However, there are few and inconsistent human data about expression and activity of this important enzyme. We investigated activity and expression of SCD1 and their relationships with liver fat (LF) content in human liver samples. Fifty subjects undergoing liver surgery were studied. SCD1 activity was estimated from the ratio of oleate (C18:1) to stearate (C18:0) within lipid subfractions. Furthermore, SCD1 mRNA expression and LF content were measured. Similarly to previous studies, we observed a strong positive correlation between LF content and the C18:1/C18:0 ratio in the combined fatty acid (FA) fractions (r = 0.96, P < 0.0001), which could be interpreted as higher SCD1 activity with increasing LF. However, hepatic SCD1 mRNA expression did not correlate with LF (r = 0.16, P = 0.13). To solve these conflicting data, we analyzed the FA composition of hepatic lipid subfractions. With increasing LF content the amount of FAs from the triglyceride (TG) fraction increased (r = 0.96, P < 0.0001), whereas the FAs from the phospholipid (PL) fraction remained unchanged (r = -0.17, P = 0.19). Of these two major lipid fractions, the C18:1/C18:0 ratio in TG was 16-fold higher than in PL. Supporting the SCD1 mRNA expression data, the C18:1/C18:0 ratio of the TG or PL fraction did not correlate with LF (r = 0.26, P = 0.12 and r = 0.08, P = 0.29). We provide novel information that SCD1 activity and mRNA expression appear not to be elevated in subjects with high LF content. We suggest that the FA composition of lipid subclasses, rather than of mixed lipids, should be analyzed to estimate SCD1 activity.

Circulating palmitoleate strongly and independently predicts insulin sensitivity in humans.

OBJECTIVE: We investigated whether palmitoleate, which prevents insulin resistance in mice, predicts insulin sensitivity in humans. RESEARCH DESIGN AND METHODS: The fasting fatty acid pattern in the plasma free fatty acid (FFA) fraction was determined in 100 subjects at increased risk for type 2 diabetes. Insulin sensitivity was estimated during an oral glucose tolerance test (OGTT) at baseline and after 9 months of lifestyle intervention and measured during the euglycemic-hyperinsulinemic clamp (n = 79). RESULTS: Circulating palmitoleate (OGTT:F ratio = 8.2, P = 0.005; clamp:F ratio = 7.8, P = 0.007) but not total FFAs (OGTT:F ratio = 0.6, P = 0.42; clamp:F ratio = 0.7, P = 0.40) correlated positively with insulin sensitivity, independently of age, sex, and adiposity. High baseline palmitoleate predicted a larger increase in insulin sensitivity. For 1-SD increase in palmitoleate, the odds ratio for being in the highest versus the lowest tertile of adjusted change in insulin sensitivity was 2.35 (95% CI 1.16-5.35). CONCLUSIONS: Circulating palmitoleate strongly and independently predicts insulin sensitivity, suggesting that it plays an important role in the pathophysiology of insulin resistance in humans.

Changes of the plasma metabolome during an oral glucose tolerance test: is there more than glucose to look at?

The oral glucose tolerance test (oGTT) is a common tool to provoke a metabolic challenge for scientific purposes, as well as for diagnostic reasons, to monitor the kinetics of glucose and insulin. Here, we aimed to follow the variety of physiological changes of the whole metabolic pattern in plasma during an oGTT in healthy subjects in a nontargeted reversed-phase ultra performance liquid chromatography coupled to electrospray ionization quadrupole time of flight mass spectrometric metabolomics approach. We detected 11,500 metabolite ion masses/individual. Applying multivariate data analysis, four major groups of metabolites have been detected as the most discriminating oGTT biomarkers: free fatty acids (FFA), acylcarnitines, bile acids, and lysophosphatidylcholines. We found in detail 1) a strong decrease of all saturated and monounsaturated FFA studied during the oGTT; 2) a significant faster decline of palmitoleate (C16:1) and oleate (C18:1) FFA levels than their saturated counterparts; 3) a strong relative increase of polyunsaturated fatty acids in the fatty acid pattern at 120 min; and 4) a clear decrease in plasma C10:0, C12:0, and C14:1 acylcarnitine levels. These data reflect the switch from beta-oxidation to glycolysis and fat storage during the oGTT. Moreover, the bile acids glycocholic acid, glycochenodeoxycholic acid, and glycodeoxycholic acid were highly discriminative, showing a biphasic kinetic with a maximum of a 4.5- to 6-fold increase at 30 min after glucose ingestion, a significant decrease over the next 60 min followed by an increase until the end of the oGTT. Lysophosphatidylcholines were also increased significantly. The findings of our metabolomics study reveal detailed insights in the complex physiological regulation of the metabolism during an oGTT offering novel perspectives of this widely used procedure.