Regulation of lipogenic enzyme expression by glucose in liver and adipose tissue: a review of the potential cellular and molecular mechanisms.

Regulation of gene expression by nutrients is an important part of the mechanisms allowing mammals to adapt to their nutritional environment. This is especially true for enzymes involved in the storage of energy such as the lipogenic and glycolytic enzymes in the liver and adipose tissue. We review in the present paper the cellular and molecular mechanisms involved in the regulation of glycolytic and lipogenic enzyme gene expression by glucose. In vivo and in vitro experiments have demonstrated that FAS and ACC gene expression is upregulated by glucose in adipose tissue, FAS, ACC and L-PK expression in the liver and ACC and L-PK expression in a pancreatic beta-cell line. This regulation involves the stimulation of their transcription. In order for glucose to act as a gene inducer, it must be metabolized. In adipose tissue, insulin increases indirectly the expression of FAS and ACC by stimulating glucose metabolism through its well-known effect on glucose transport. In the liver, the action of insulin is also indirect by allowing the expression of glucokinase and hence by increasing glucose metabolism. In the liver, fructose has a potentiating effect on the stimulation of gene expression by glucose through its stimulatory effect on glucokinase activity. Several evidences suggest that glucose-6-phosphate is the signal metabolite: (i) the effect of glucose is mimicked by 2-deoxyglucose (a glucose analogue whose metabolism stops after its phosphorylation by hexokinase) in adipose tissue and beta-cell line but not in the liver in which 2-deoxyglucose-6-phosphate does not accumulate, (ii) intracellular glucose-6-phosphate concentration varies in parallel with ACC, FAS and L-PK mRNA concentrations in liver, adipose tissue and beta-cell line, (iii) in vivo, the kinetics of hexose-phosphate fits with the time-related pattern of gene induction. Glucose response elements have been characterized on three genes, L-PK, S14 (a gene which codes for a protein of unknown function but which is directly related to lipogenesis) and FAS. These glucose response elements have all in common the presence of a sequence 5'-CACGTG-3' which binds a transcription factor of the basic domain, helix-loop-helix, leucine zipper family called USF/MLTF, although the organization of the overall glucose response element probably differs from one gene to another. The mechanisms linking glucose-6-phosphate to the glucose responsive transcription complex are presently largely unknown.