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Brain Trauma Disrupts Hepatic Lipid Metabolism: Blame It on Fructose?

ABSTRACT: SCOPE:The action of brain disorders on peripheral metabolism is poorly understood. The impact of traumatic brain injury (TBI) on peripheral organ function and how TBI effects can be influenced by the metabolic perturbation elicited by fructose ingestion are studied. METHODS AND RESULTS:It is found that TBI affects glucose metabolism and signaling proteins for insulin and growth hormone in the liver; these effects are exacerbated by fructose ingestion. Fructose, principally metabolized in the liver, potentiates the action of TBI on hepatic lipid droplet accumulation. Studies in isolated cultured hepatocytes identify GH and fructose as factors for the synthesis of lipids. The liver has a major role in the synthesis of lipids used for brain function and repair. TBI results in differentially expressed genes in the hypothalamus, primarily associated with lipid metabolism, providing cues to understand central control of peripheral alterations. Fructose-fed TBI animals have elevated levels of markers of inflammation, lipid peroxidation, and cell energy metabolism, suggesting the pro-inflammatory impact of TBI and fructose in the liver. CONCLUSION:Results reveal the impact of TBI on systemic metabolism and the aggravating action of fructose. The hypothalamic-pituitary-growth axis seems to play a major role in the regulation of the peripheral TBI pathology.

SUBMITTER: Rege SD

PROVIDER: S-EPMC6763319 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Brain Trauma Disrupts Hepatic Lipid Metabolism: Blame It on Fructose?

Rege Shraddha D SD Royes Luiz L Tsai Brandon B Zhang Guanglin G Yang Xia X Gomez-Pinilla Fernando F

Molecular nutrition & food research 20190606 15

<h4>Scope</h4>The action of brain disorders on peripheral metabolism is poorly understood. The impact of traumatic brain injury (TBI) on peripheral organ function and how TBI effects can be influenced by the metabolic perturbation elicited by fructose ingestion are studied.<h4>Methods and results</h4>It is found that TBI affects glucose metabolism and signaling proteins for insulin and growth hormone in the liver; these effects are exacerbated by fructose ingestion. Fructose, principally metabol ...[more]

PMID: 31087499

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Project description:ObjectiveIncreased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption.MethodsWe tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects.ResultsHepatic expression of ChREBP-? and Fgf21 acutely increased 2-fold and 3-fold, respectively, following fructose gavage, and this was accompanied by increased circulating FGF21. The acute increase in circulating FGF21 following fructose gavage was absent in ChREBP knockout mice. Induction of ChREBP-? and its glycolytic, fructolytic, and lipogenic gene targets were attenuated in FGF21 knockout mice fed high-fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis a, 30% reduction VLDL secretion, and a 25% reduction in liver fat compared to fructose-fed controls. In human subjects, serum FGF21 correlates with de novo lipogenic rates measured by stable isotopic tracers (R = 0.55, P = 0.04) consistent with conservation of a ChREBP-FGF21 interaction. After 8 weeks of high-fructose diet, livers from FGF21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation; whereas, this did not occur in controls.ConclusionsIn summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis.

Dataset Information

Brain Trauma Disrupts Hepatic Lipid Metabolism: Blame It on Fructose?

Publications

Brain Trauma Disrupts Hepatic Lipid Metabolism: Blame It on Fructose?

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