Fructose surges damage hepatic adenosyl-monophosphate-dependent kinase and lead to increased lipogenesis and hepatic insulin resistance

Abstract Fructose may be a key contributor to the biochemical alterations which promote the metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM): a) its consumption in all forms but especially in liquid form has much increased alongside with incidence of MetS conditions; b) it is metabolized almost exclusively in the liver, where it stimulates de novo lipogenesis to drive hepatic triglyceride (TG) synthesis which c) contributes to hepatic insulin resistance and NAFLD [1–6] . The specifics of fructose metabolism and its main location in the liver serve to explain many of the possible mechanisms involved. It also opens questions, as the consequences of large increases in fructose flux to the liver may wreak havoc with the regulation of metabolism and would produce two opposite effects (inhibition and activation of AMP dependent kinase-AMPK) that would tend to cancel each other. We posit that 1) surges of fructose in the portal vein lead to increased unregulated flux to trioses accompanied by unavoidable methylglyoxal (MG) production, 2) the new, sudden flux exerts carbonyl stress on the three arginines on the γ subunits AMP binding site of AMPK, irreversible blocking some of the enzyme molecules to allosteric modulation, 3) this explains why, even when fructose quick phosphorylation increases AMP and should therefore activate AMPK, the effects of fructose are compatible with inactivation of AMPK, which then solves the apparent metabolic paradox. We put forward the hypothesis that fructose loads, via the increase in MG flux worsens the fructose-driven metabolic disturbances that lead to unrestricted de novo lipogenesis, fatty liver and hepatic insulin resistance. It does so via the silencing of AMPK. Our hypothesis is testable and if proven correct will shed some further light on fructose metabolism in the liver. It will also open new roads in glycation research, as modulation of MG catabolism may be a way to dampen the damage. Research on this area may have important therapeutic potential, e.g., more momentum to find new and improved carbonyl quenchers, new insights on the action of metformin, more evidence for the role of GAPDH inactivation due to mitochondrial overload in diabetes complications. AMPK plays a central role in metabolism, and its function varies in different tissues. For that reason, synthetic activators will always stumble with unwanted or unpredictable effects. Preventing MG damage on the protein c