Regulation of gene expression in adipose cells by polyunsaturated fatty acids.
In fat cells polyunsaturated fatty acids are both substrates for, and products of, triacylglycerol metabolism. Dietary fatty acids are efficiently incorporated into the triacylglycerol droplet under lipogenic conditions while rapidly mobilizing them during lipolytic stimulation. Hence, the flux and magnitude of the fatty acid pool in adipocytes is constantly changing in response to hormonal, metabolic and genetic determinants. Due to the rapidly changing flux of fatty acids, the majority of genes encoding enzymes and proteins of lipid metabolism are largely refractory to long-term regulatory control by fatty acids. Only at extremes of high or low lipid levels, or under pathophysiological conditions, do adipose genes respond by up- or down-regulating gene expression. Despite the lack of responsiveness to lipids in adipose tissue, a surprisingly large number of genes have been characterized recently as lipid responsive when assayed in heterologous systems. These observations suggest an endogenous negative element exists in the lipid signaling pathway in adipocytes. The major intracellular lipid binding protein in adipose cells is the adipocyte lipid binding protein (ALBP), the product of the aP2 gene. This protein is 15 kDa, abundant and found exclusively in the cytoplasm of adipocytes. The protein binds fatty acids and related lipids in a 1:1 stoichiometry within a large water filled interior cavity. The lipid binding protein forms high affinity associations with polyunsaturated fatty acids such as arachidonic acid (Kd approximately 250 nM) but not with prostaglandins of the E, D or J series (Kd > 4 microM). The upstream region of the aP2 gene contains a peroxisome-proliferator activated receptor response element which associates with PPARs to regulate its expression. A positive autoregulatory circuit exists to upregulate lipid binding protein expression when polyunsaturated fatty acid levels are increased. Analysis of adipose tissue from aP2 null animals generated by a targeted disruption revealed that the partial loss of ALBP expression in heterozygotes and complete lack of ALBP in the nulls was accompanied by a compensatory up-regulation of the keratinocyte lipid binding protein. However, the total amount of lipid binding protein in the nulls was less than 15% that in the wild type littermates. No evidence was found for upregulation of other lipid binding proteins such as the heart FABP or liver FABP. In aP2 nulls, the fatty acid composition was unaltered but the mass of fatty acid per gram tissue more than doubled relative to wild type. In heterozygotes, the level of fatty acid was intermediate to that of wild-type and nulls, consistent with an intermediate level of lipid binding protein. These results indicate that the fatty acid pool level in adipocytes is inversely correlated with the amount of lipid binding protein. Since prostaglandin biosynthesis is dependent upon polyunsaturated fatty acid substrates, the intracellular lipid binding proteins control accessibility of substrates of the prostanoid pathway. Intracellular lipid binding proteins therefore are negative elements in polyunsaturated fatty acid control of gene expression.
Bernlohr
D A
DA
Department of Biochemistry, University of Minnesota, St. Paul 55108-1022, USA. david-b@biosci.cbs.umn.edu
Coe
N R
NR
Simpson
M A
MA
Hertzel
A V
AV
D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005231:Fatty Acids, Unsaturated / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018996:Myelin P2 Protein / Q000235:genetics; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D015854:Up-Regulation
D002352:Carrier Proteins; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005231:Fatty Acids, Unsaturated; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins