Comparative Effects of Fructose and Glucose on Lipogenic Gene Expression and Intermediary Metabolism in HepG2 Liver Cells

Abstract

Consumption of large amounts of fructose or sucrose increases lipogenesis and circulating triglycerides in humans. Although the underlying molecular mechanisms responsible for this effect are not completely understood, it is possible that as reported for rodents, high fructose exposure increases expression of the lipogenic enzymes fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC-1) in human liver. Since activation of the hexosamine biosynthesis pathway (HBP) is associated with increases in the expression of FAS and ACC-1, it raises the possibility that HBP-related metabolites would contribute to any increase in hepatic expression of these enzymes following fructose exposure. Thus, we compared lipogenic gene expression in human-derived HepG2 cells after incubation in culture medium containing glucose alone or glucose plus 5 mM fructose, using the HBP precursor 10 mM glucosamine (GlcN) as a positive control. Cellular metabolite profiling was conducted to analyze differences between glucose and fructose metabolism. Despite evidence for the active uptake and metabolism of fructose by HepG2 cells, expression of FAS or ACC-1 did not increase in these cells compared with those incubated with glucose alone. Levels of UDP-N-acetylglucosamine (UDP-GlcNAc), the end-product of the HBP, did not differ significantly between the glucose and fructose conditions. Exposure to 10 mM GlcN for 10 minutes to 24 hours resulted in 8-fold elevated levels of intracellular UDP-GlcNAc (P<0.001), as well as a 74–126% increase in FAS (P<0.05) and 49–95% increase in ACC-1 (P<0.01) expression above controls. It is concluded that in HepG2 liver cells cultured under standard conditions, sustained exposure to fructose does not result in an activation of the HBP or increased lipogenic gene expression. Should this scenario manifest in human liver in vivo, it would suggest that high fructose consumption promotes triglyceride synthesis primarily through its action to provide lipid precursor carbon and not by activating lipogenic gene expression.

Ingestão de açúcar de adição por estudantes da área da saúde em uma instituição de ensino de Viçosa, Brasil

“…Além disso, o elevado teor de frutose dessas bebidas pode aumentar o risco de desenvolvimento de doenças cardiovasculares devido à dislipidemia, aumento da gordura visceral, hipertensão arterial e hiperuricemia 4,7 . Outro desfecho metabólico importante tem sido o observado sobre os níveis plasmáticos de lipídios em adultos e crianças com ingestão elevada de açúcar de adição e frutose na dieta habitual 30 . Em um estudo com adultos americanos com ingestão de açúcar de adição acima de 10% do valor calórico total (VCT) da dieta foram observados níveis plasmáticos baixos de HDL colesterol e elevados níveis de triglicerídeos e LDL colesterol, representando um perfil lipídico de maior risco para o desenvolvimento de doença coronariana 31 .…”

“…O fígado é o principal sítio da lipogênese de novo, e é responsável pela utilização da maior parte da frutose da dieta que alcança a veia porta. Entretanto, o mecanismo molecular subjacente ao aumento da produção hepática de lipídios em resposta a dieta de alto teor de frutose permanece desconhecido 30,32 . Quanto aos micronutrientes analisados, a ingestão de cálcio representou 68,6% da recomendação 33 para esta faixa etária.…”

Lipogenesis in Huh7 cells is promoted by increasing the fructose: Glucose molar ratio

“…Since fructose is more efficiently utilized intracellularly, as compared with glucose, it may provide a more readily available substrate for lipid synthesis [26] . Interestingly, one recent study failed to demonstrate any effects of fructose on regulating hepatocellular lipogenic genes, thus providing further, indirect evidence linking the lipogenic role of this monosaccharide to its ability to provide increased amounts of carbon fragments for lipid synthesis [27] . The present results extend this observation by demonstrating that lipogenesis, in cultured hepatocytes, is not solely related to the provision of carbon precursors, since all incubations contained similar total monosaccharide concentrations.…”

The Role of Liver X Receptor in Hepatic de novo Lipogenesis and Cross-Talk with Insulin and Glucose Signaling

“…Fructose increase hepatic hexosamine signaling (Hirahatake et al, 2011) and induce SREBP1c and ChREBP expression in hepatic cells (Matsuzaka et al, 2004;Haas et al, 2012;Koo et al, 2009), which may, in part be mediated by LXR. The response of LXR to glucose has been debated (Lazar & Willson, 2007), but a recent study support the notion of LXR as a glucose/fructose sensor as high sucrose fed mice exhibit elevated hepatic expression of SREBP1c and increased TG levels, which was not observed in LXR/ double knock out mice (Korach-Andre et al, 2011).…”