Abstract
A high carbohydrate diet up-regulates the transcription of enzymes of triglyceride biosynthesis (lipogenesis) in the mammalian liver. This treatment stimulates hepatic insulin signaling, leading to transcription of sterol regulatory element-binding protein-1c (SREBP-1c). SREBP-1c has been implicated as a major factor that up-regulates lipogenic genes in response to carbohydrate feeding. However, we presented evidence for another factor, carbohydrate response factor, which is also involved in this response, and we proposed a model wherein SREBP-1c and carbohydrate response factor are independent transcription factors that act in response to insulin and glucose, respectively. In this study, we examined the contribution of SREBP-1c to the expression of lipogenic genes in glucose- and insulin-treated primary rat hepatocytes using an inducible adenovirus system. We found that SREBP-1c overexpression leads to a modest induction of fatty acid synthase, S(14), and acetyl-CoA carboxylase mRNAs to 20% (fatty acid synthase), 10% (S(14)), and 5% (acetyl-CoA carboxylase) of the induction seen by high glucose and insulin treatment. Restoring insulin to cells overexpressing SREBP-1c did not further increase these mRNA levels. In contrast, adenovirus-expressed SREBP-1c did not induce pyruvate kinase mRNA, suggesting that induction of this gene is SREBP-1c-independent. SREBP-1c does indeed play a role in the induction of lipogenic enzyme genes in response to insulin treatment, but it is not sufficient for the induction seen when hepatocytes are treated with insulin and high glucose.
Highlights
The synthesis of triglycerides is nutritionally regulated
We found that SREBP-1c overexpression leads to a modest induction of fatty acid synthase, S14, and acetyl-CoA carboxylase mRNAs to 20%, 10% (S14), and 5% of the induction seen by high glucose and insulin treatment
We report that SREBP-1c plays an important role as a downstream regulator of insulin signaling in the induction of lipogenic enzyme genes, but that its expression alone is not sufficient for the induction seen with high glucose and insulin treatment in hepatocytes
Summary
When mammals are fed a high carbohydrate/low fat diet, the expression of genes involved in triglyceride formation (lipogenesis) is induced. This induction occurs primarily at the transcriptional level in the liver and adipose tissue, the major sites of lipogenesis. It is difficult to determine the respective roles of these two pathways in the whole animal where both hormonal levels and substrate availability fluctuate following a meal For this reason, cultured primary hepatocytes have proven useful in mimicking the lipogenic response seen in a fed animal by treatment with controlled levels of the two signals, glucose and insulin [4].
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