Insulin resistance in metabolic syndrome – lipogenesis

To achieve the second objective, evaluating mechanisms via which fructose promotes hepatic triglyceride biosynthesis, the study by Huang et al. [7] firstly compared effects of glucose and fructose treatments on core enzymes involved in triglyceride biosynthesis in hepatocytes. Although various metabolic pathways (e.g. glycolysis and pyruvate oxidation) are involved in triglyceride biosynthesis in the liver, a core enzyme that the study used is acetyl CoA carboxylase (ACC). ACC catalyzes the transformation of acetyl CoA to malonly-CoA before the latter’s conversion to palmitate by the action of fatty acid sythetase [7]. In presence of fructose, the study found out that the physiologic role of glucose in stimulating the expression of activated ACC was impaired. Decreased expression of serine-phosphorylated hormone sensitive lipase and adipose triglyceride lipase – two enzymes critical in the hydrolysis of triglycerides – was also observed in fructose-treated cells  as compared to the cells treated only with glucose. Evaluating these effects in vivo using mice fed with fructose and glucose diets, the study found out that dietary fructose adversely affected glucose disposal and insulin secretion processes. Further, the in vivo assays buttressed the suggestion of increased triglyceride accumulation in the liver cells following consumption of fructose-rich diet [7].

Expounding on the mechanisms involved in fructose-mediated lipogenesis, is a review published in 2011 [8]. In this review, Samuel identifies potential promoters of fructose-induced lipogenesis to alteration of enzyme activity or the fructose regulation of transcription of genes that code for proteins involved in lipogenesis. One of the enzymes identified in the review is pyruvate dehydrogenase (PDH), an enzyme that catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA. Fructose action in this respect is thought to be inhibition of PDH kinase (PDK) activity, an enzyme that inactivates PDH [8]. Accordingly, such inhibition by fructose would result in prolonged activity of PDH thus contributing one of the substrates (acetyl-CoA) required for the synthesis of triglycerides. Despite such suggestions that fructose inhibits PDK, the mechanism through which such inhibition proceeds remains unclear, and the extent of regulation may not be replicated in humans or primates [8]. Additionally, insulin may be a more potent regulator of PDH activity than fructose [8], thus necessitating further assays on how PDK functions in fructose-induced lipogenesis. This is particularly important, since some inhibitors of PDK are suggested as potential remedies of type II diabetes – a condition associated with insulin resistance – via their action of decreasing substrates for gluconeogenesis through increased pyruvate oxidation [9].

Apart from the enzyme, the review [8] identifies two lipogenesis-transcriptional elements where activity of fructose may promote lipogenesis. Firstly, fructose is suggested to promote activity of “transcription co-activator, peroxisome proliferator activated receptor (PPAR)-ɣ coactivactor (PGC)1ß” [8, p. 62]. PGC1ß functions as a co-activator of nuclear receptor leading to increased activities of transcription factors such as PPARɣ, PPARα and liver X receptor (LXR), by binding to and transactivating sterol regulatory element binding protein 1 (SREBP1) [8]. In presence of fructose PGC1ß, is suggested as a core component required for the regulation of the actions of SREBP1 and LXR, thus the promotion of lipogenesis [8]. When PGC1ß activity is inhibited (e.g. following attenuation of its expression) the cells response to insulin has been suggested to improve [8]. Accordingly, effect of fructose in this respect would be promoting expression of PGC1ß thus promoting lipogenesis as opposed to glucose disposal

A second transcription element suggested to explain lipogenic activity of fructose is X-box binding protein (XBP)1 [8]. XBP1 is involved in regulation of expression of various proteins including the enzymes that participate in lipogenesis. When fed with fructose, mice have been shown to increase the expression of XBP1 mRNA thus protein expression [8]. When XBP1 expression is inhibited (e.g. following deletion) subsequent decrease in SREBP1 expression and, further, the expression of core lipogenic enzyme decreases lipogenesis and triglyceride synthesis and secretion [8]. In this respect, the effect of fructose would thus be promoting expression of XBP1 thus eventually resulting in increased lipogenesis and triglyceride synthesis and accumulation. However, just as was the case with fructose induction of lipogenesis through its inhibition of PDK, the suggested mechanisms implicating fructose in transcriptional regulation are not well established. Go to leptin resistance.

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