Fructose and metabolic health: governed by hepatic glycogen status?

J Physiol 597.14 (2019) pp 3573–3585

Hengist A, Koumanov F and Gonzalez JT.

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Objective

• To
  present the hypothesis that hepatic glycogen stores may regulate metabolic
  responses to fructose ingestion and could therefore be a target to prevent
  or mitigate the negative metabolic effects of fructose intake.

Background

• Fructose is a commonly ingested dietary sugar,
  which has been implicated in playing a particularly harmful role in the
  development of metabolic disease.
• Fructose is primarily metabolized by the liver
  in humans, and increases rates of hepatic de novo lipogenesis via numerous
  mechanisms: 1) by altering transcriptional and allosteric regulation; 2)
  interfering with cellular energy sensing, and 3) disrupting the balance between
  lipid synthesis and lipid oxidation.
• Considering that fructose has the capacity to
  upregulate hepatic glycogen storage, and replenish these stores more
  readily following glycogen depleting exercise, the idea that hepatic
  glycogen storage and hepatic de novo lipogenesis are linked is a
  considerable prospect.

Methods

• No methodology was reported in this review.

Findings

• In
  current evidence, insulin response appears to be the main factor dictating
  acute responses to fructose ingestion, but longer-term detriments are
  characterized by increased hepatic lipogenesis. This suggests that dietary
  fructose ingestion may be particularly harmful for health in certain contexts,
  for example when humans are in a positive energy balance and/or low energy
  turnover.
• Evidence
  also suggests that the mechanisms of hepatic lipid uptake, synthesis, and
  oxidation are likely the most important targets to regulate metabolic
  health in relation to hepatic lipid metabolism, as the downstream partitioning
  to VLDL secretion or hepatic TAG storage are both detrimental to metabolic
  health when excessively stimulated.
• Assuming
  the authors’ hepatic glycogen hypothesis is correct, the ingestion of
  fructose when hepatic glycogen stores are already saturated would
  stimulate lipogenesis to a greater extent than when hepatic glycogen
  stores are low. If glycogen is being utilized at a rate high enough to overcome
  net glycogen synthesis, despite fructose intake, then theoretically this
  should reduce hepatic DNL and VLDL output.
• An
  inability to further synthesise glycogen upregulates hepatic DNL and,
  considering that fructose ingestion increases both DNL and hepatic
  glycogen synthesis, glycogen stores may play a key role in determining the
  metabolic responses to fructose ingestion. The corollary is that negative
  metabolic effects of fructose intake are most likely to manifest when
  hepatic glycogen stores are saturated.

Conclusions

• This
  hypothesis provides a rationale for striving to consider nutrient–physical
  activity interactions in physiology research, and to target turnover
  and/or utilization of hepatic glycogen stores to improve metabolic health.
• Future
  research should strive to take an integrated approach towards
  understanding physiological responses to nutrients.  Where possible, researchers should
  strive to understand the effects of fructose ingestion (or any other
  nutrient) in the context of mediating factors. Measuring physical activity
  energy expenditure, type, timing and intensity are all useful towards
  understanding the physiological effects of nutrient ingestion.

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