Role of AMP-activated protein kinase gamma 3 genetic variability in glucose and lipid metabolism in non-diabetic whites.
OBJECTIVE
AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that acts as an intracellular fuel sensor, directing multiple metabolic pathways in a catabolic direction in times of nutrient shortage. In humans, three different gamma-subunits (gamma(1), gamma(2), gamma(3)) have been identified as AMPK regulators. The AMPKgamma3 (protein kinase, AMP-activated, gamma 3 non-catalytic subunit, PRKAG3) isoform plays a role in gene regulation in glucose/lipid metabolism and skeletal muscle glycogen content. We investigated whether PRKAG3, in addition to being expressed in skeletal muscle, is also expressed in human liver. We also investigated whether genetic variance in PRKAG3 is associated with glucose and/or lipid metabolism in non-diabetic whites.


METHODS
After sequencing a screening cohort (n = 50) in the PRKAG3 locus, we genotyped 1061 participants for frequently found single nucleotide polymorphisms (SNPs). Association analyses between genotypes/haplotypes and metabolic traits were carried out.


RESULTS
We detected PRKAG3 expression in human liver and skeletal muscle. Two SNPs (rs692243, rs6436094) with minor allele frequencies of 0.16 and 0.26 respectively and in moderate linkage disequilibrium (D' = 0.92; r (2) = 0.47) were found. rs692243 (C/G) confers a Pro71Ala mutation, while rs6436094 (A/G) is located in the 3' untranslated region. No associations with prediabetic traits such as body fat distribution, insulin resistance or insulin secretion were found (p > 0.15 for all). However, the minor alleles of both SNPs were significantly associated with higher serum LDL-cholesterol and apolipoprotein (Apo) B-100 levels (rs692243: CG:LDL 4.3%, ApoB-100 3.4%; GG:LDL 7.6%, ApoB-100 5.4%; p = 0.008 and p = 0.01 respectively; rs6436094: AG:LDL 3.3%, ApoB-100 1.7%; GG:LDL 11.3%, ApoB-100 11.1%; p = 0.009 and p = 0.05 respectively; dominant model). The GG/GG diplotype homozygous for both minor SNP alleles displayed the highest LDL-cholesterol among all frequent diplotypes (p = 0.059).


CONCLUSIONS
While genetic variability in PRKAG3 does not seem to have a major effect on glucose metabolism, it may play an important role in lipoprotein metabolism in humans.
Weyrich
P
P
Department of Internal Medicine, Division of Endocrinology, Metabolism, Pathobiochemistry and Clinical Chemistry, University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.
Machicao
F
F
Staiger
H
H
Simon
P
P
Thamer
C
C
Machann
J
J
Schick
F
F
Guirguis
A
A
Fritsche
A
A
Stefan
N
N
Häring
H-U
HU
D055372:AMP-Activated Protein Kinases; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D000078790:Insulin Secretion; D008055:Lipids / Q000097:blood*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000201:enzymology; D009097:Multienzyme Complexes / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044465:White People / Q000235:genetics
D001786:Blood Glucose; D018076:DNA, Complementary; D007328:Insulin; D008055:Lipids; D008074:Lipoproteins; D009097:Multienzyme Complexes; D021122:Protein Subunits; C526222:PRKAG1 protein, human; C526225:PRKAG3 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose
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