EASD 2022: Modulators of Gluco and Lipotoxicity

The lecture discusses fructose and glucose as precursors for the synthesis of toxic fatty acids. The contribution of fructose and glucose with respect to lipogenic precursor pool and the product of normal lipogenesis, intestinal toxicity and ways to prevent it.

One of the pathogenic mechanisms for non-alcoholic fatty liver disease or NAFLD is the increase in the normal lipogenesis. The synthesis of lipids by the liver directly contributes to increased fat. In addition, the intermediates of lipogenesis block beta oxidation which can exacerbate the fatty liver.

Fructose should never be considered as an isolated nutrient because even with a high fructose, there's always a significant amount of glucose that can be ingested at the same time in fructose rich food such as corn syrup. This fructose cooperates with hepatic glucose metabolism in several ways.

The phosphorylation of glucose by the liver glucokinase needs to be freed from its repressor protein and be exported to the cytosol. This allows the glucose to be phosphorylated and fructose potentiates this effect of glucose metabolism.

According to tracer methodology with uniformly carbon 13 fructose tracers, fructose forms the uniformly labeled triphosphates which is converted to uniformly labeled acetyl coA. These COA units are synthesized and the first product is palmitate.  It can elongate and form stearate. In terms of lipotoxicity, such saturated fatty acids are lipotoxic with fructose contributing more to the lipotoxic fatty acids than to the mono and unsaturated ones. Fructose provides a significantly higher contribution of acetyl coA for de novo synthesis compared to exogenous glucose and favors the synthesis of saturated toxic fatty acids compared to unsaturated ones.  In mice fed with high fat +high sugar diet, exogenous fructose contributed a significantly higher fraction of acetyl-CoA to de novo synthesis of saturated fatty acids (palmitate +strearate) compared with monosaturated fatty acids(oleate+palmitoleate). Hepatic fructose metabolism results in a more lipotoxic profile of newly synthesized fatty acids compared to that of glucose.

The kidney and the intestine are able to produce glucose in blood and this increased participation of the kidney and the intestine may occur in a fed state, contributing to hyperglycemia and glucose toxicity. In the glucose production via the manipulation of the sympathetic and parasympathetic system, the brain is able to control hepatic glucose production.

The location where gluconeogenesis takes place matters. When it occurs in the liver it has deleterious effects causing insulin resistance and glucose toxicity.

But the systems of sensing glucose from the gut and the brain signals are able to initiate, there is a beneficial glucose production with anti gluco lipotoxic action. This benefit of intestinal lipogenesis indicates that it is sufficient to induce gluconeogenesis in the gut to generate the benefit, even in the absence of a healthy diet.