A Thr94Ala mutation in human liver fatty acid-binding protein contributes to reduced hepatic glycogenolysis and blunted elevation of plasma glucose levels in lipid-exposed subjects.
Liver fatty acid-binding protein (L-FABP) is a highly conserved key factor in lipid metabolism. Amino acid replacements in L-FABP might alter its function and thereby affect glucose metabolism in lipid-exposed subjects, as indicated by studies in L-FABP knockout mice. Amino acid replacements in L-FABP were investigated in a cohort of 1,453 Caucasian subjects. Endogenous glucose production (EGP), gluconeogenesis, and glycogenolysis were measured in healthy carriers of the only common Thr(94)-to-Ala amino acid replacement (Ala/Ala(94)) vs. age-, sex-, and BMI-matched wild-type (Thr/Thr(94)) controls at baseline and after 320-min lipid/heparin-somatostatin-insulin-glucagon clamps (n = 18). Whole body glucose disposal was further investigated (subset; n = 13) using euglycemic-hyperinsulinemic clamps without and with lipid/heparin infusion. In the entire cohort, the only common Ala/Ala(94) mutation was significantly associated with reduced body weight, which is in agreement with a previous report. In lipid-exposed, individually matched subjects there was a genotype vs. lipid-treatment interaction for EGP (P = 0.009) driven mainly by reduced glycogenolysis in Ala/Ala(94) carriers (0.46 +/- 0.05 vs. 0.59 +/- 0.05 mgxkg(-1)xmin(-1), P = 0.013). The lipid-induced elevation of plasma glucose levels was smaller in Ala/Ala(94) carriers compared with wild types (P < 0.0001). Whole body glucose disposal was not different between lipid-exposed L-FABP genotypes. In summary, the Ala/Ala(94)-mutation contributed significantly to reduced glycogenolysis and less severe hyperglycemia in lipid-exposed humans and was further associated with reduced body weight in a large cohort. Data clearly show that investigation of L-FABP phenotypes in the basal overnight-fasted state yielded incomplete information, and a challenge test was essential to detect phenotypical differences in glucose metabolism between L-FABP genotypes.
Weickert
Martin O
MO
Dept. of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. m.weickert@dife.de
Loeffelholz
Christian V
CV
Roden
Michael
M
Chandramouli
Visvanathan
V
Brehm
Attila
A
Nowotny
Peter
P
Osterhoff
Martin A
MA
Isken
Frank
F
Spranger
Jochen
J
Landau
Bernard R
BR
Pfeiffer
Andreas F H
AF
Möhlig
Matthias
M
D000409:Alanine / Q000235:genetics; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001835:Body Weight / Q000235:genetics; D015331:Cohort Studies; D050556:Fatty Acid-Binding Proteins / Q000235:genetics*; D005260:Female; D005838:Genotype; D015309:Glucose Clamp Technique; D050261:Glycogenolysis / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008055:Lipids / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D013912:Threonine / Q000235:genetics
D001786:Blood Glucose; D050556:Fatty Acid-Binding Proteins; D008055:Lipids; D013912:Threonine; D000409:Alanine