Molecular Aspects of Fructose Metabolism and Metabolic Disease

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Introduction

Dr. Mark Herman, Chief of the Section of Endocrinology at Baylor College of Medicine, presents an overview of his lab's research over the past decade, focusing on the molecular aspects of fructose metabolism and its contribution to metabolic disease. The presentation emphasizes that while sugar consumption, particularly from sugar-sweetened beverages (SSBs), is epidemiologically linked to adverse metabolic health outcomes globally, the specific mechanisms remain somewhat controversial and uncertain.

The Epidemiological and Mechanistic Puzzle of Sugar Consumption

A 2015 study by Dariush Mozaffarian estimated a significant contribution of SSB consumption to excess mortality in Mexico, a country with high per capita SSB intake. While Dr. Herman advises caution regarding the precise magnitude of this impact, he acknowledges the potential significance of SSB consumption on metabolic health. Epidemiological studies consistently associate SSB consumption with an increased risk of type 2 diabetes, fatty liver disease, and other cardio-metabolic risk factors. However, this association is not consistently observed with other dietary sugar sources like fruit, which are generally considered healthful. This discrepancy highlights the complexity of the issue and suggests that other factors, such as lifestyle choices that often correlate with SSB consumption, might play a role. Furthermore, a clearer understanding of the precise mechanisms by which excessive sugar consumption leads to metabolic disease is needed to better interpret these epidemiological findings and develop targeted interventions beyond simply reducing sugar intake.

Fructose as a Key Player in Metabolic Disruption

While sucrose, the common dietary sugar, is a disaccharide composed of glucose and fructose, Dr. Herman posits that the fructose component may be particularly deleterious. Studies from the 1960s and 1970s demonstrated that very high doses of fructose in animal diets could rapidly induce features of cardio-metabolic disease. Dr. Gerald Reaven, who coined the term "syndrome X" (now known as metabolic syndrome or cardio-metabolic disease), used high-fructose diets (60% of calories) as a model to illustrate how a single nutrient in excess could induce a cluster of metabolic abnormalities. However, Dr. Herman notes that these high fructose levels significantly exceed those typically found in Western diets, raising questions about the direct applicability of these early findings to common dietary exposures. Nevertheless, these studies underscore the potential of high fructose intake to disrupt metabolic homeostasis and highlight the importance of dose-dependent effects in this field.

Divergent Metabolic Pathways of Glucose and Fructose

A fundamental aspect of understanding fructose's impact lies in recognizing its distinct metabolic pathway compared to glucose. In hepatocytes, glucose is transported across the cell membrane primarily by GLUT2 and is phosphorylated to glucose-6-phosphate by glucokinase. Notably, the Km of glucokinase for glucose is within the physiological range of circulating glucose levels, allowing glucose uptake proportional to its concentration.

In contrast, fructose is transported by a combination of GLUT2 and GLUT5, depending on the cell type and species, and is rapidly phosphorylated by ketohexokinase to fructose-1-phosphate. The crucial difference lies in the significantly lower Km of ketohexokinase for fructose (0.8 mM) compared to glucokinase for glucose (around 10 mM). This low Km ensures that fructose, upon entering the cell, is almost immediately phosphorylated, leading to very low intracellular free fructose concentrations and potentially high levels of fructose-1-phosphate. Fructose-1-phosphate is then cleaved by aldolase B into glyceraldehyde and dihydroxyacetone phosphate. Dihydroxyacetone phosphate enters glycolysis and gluconeogenesis directly, while glyceraldehyde is phosphorylated by triokinase to glyceraldehyde-3-phosphate, also feeding into these central metabolic pathways. This rapid and largely unregulated entry of fructose-derived carbons into metabolic pathways distinguishes it from glucose metabolism.

First-Pass Hepatic Metabolism of Fructose: A Critical Difference

Another key distinction between glucose and fructose metabolism is their handling after oral ingestion. A large glucose load is primarily absorbed in the small intestine and bypasses significant intestinal metabolism before reaching the portal vein and subsequently the systemic circulation. The liver has limited efficiency in extracting circulating glucose, which leads to a rise in peripheral blood glucose levels and triggers insulin secretion for glucose disposal in peripheral tissues. This forms the basis of the glucose tolerance test.

Fructose, however, undergoes extensive first-pass metabolism in the enterocytes and the liver. Enterocytes express ketohexokinase and can convert a substantial portion of ingested fructose into fructose-1-phosphate. Studies have shown that after a 30-gram fructose load, millimolar concentrations of fructose can be found in the portal vein, while peripheral concentrations remain very low (around 0.1 mM), indicating a significant hepatic extraction. Elegant tracer studies by Luuke Tappy in 2019 estimated that only about 14% of a large oral fructose load escapes the gut and liver first pass.

The Case of Benign Essential Fructosuria: Evidence for the Importance of Fructose Metabolism

A compelling "natural experiment" highlighting the importance of fructose metabolism in its potential adverse effects is the condition of benign essential fructosuria, caused by loss-of-function mutations in ketohexokinase. Individuals with this condition have high circulating fructose levels after ingesting fructose-containing sugars, yet they exhibit no increased risk of obesity, hypertension, diabetes, or other features associated with cardio-metabolic disease. This observation strongly suggests that fructose metabolism, initiated by ketohexokinase, is a prerequisite for the development of fructose-induced metabolic dysfunction.

Proposed Mechanisms Linking Fructose Metabolism to Metabolic Disease

Based on the understanding that fructose metabolism is crucial for its potential detrimental effects, Dr. Herman outlines several non-mutually exclusive hypotheses regarding the mechanisms involved:

• Energetic Stress and Uric Acid Production: The rapid phosphorylation of fructose by ketohexokinase consumes significant amounts of ATP, potentially leading to cellular ATP depletion and an increase in AMP. Elevated AMP can activate adenosine deaminase, the rate-limiting enzyme in purine degradation, resulting in increased uric acid production and a higher risk of gout. This aligns with the observed association between increased fructose consumption and gout.
• Substrate Provision for Biosynthetic Pathways: The fructose-derived triose phosphates can serve as substrates for various biosynthetic processes:
  • Gluconeogenesis: Conversion back to glucose-6-phosphate can contribute to increased hepatic glucose production and potentially hyperglycemia and insulin resistance.
  • Lipogenesis: Conversion to malonyl-CoA can fuel increased de novo lipogenesis in the liver, contributing to fatty liver disease.
• Activation of Signaling Systems: Fructose metabolites may directly or indirectly activate signaling pathways that regulate diverse cellular processes, ultimately contributing to cardio-metabolic disease. Dr. Herman's lab focuses on this third aspect.

The Role of Carbohydrate Responsive Element Binding Protein (CHRBP)

Dr. Herman's laboratory has been particularly interested in the role of Carbohydrate Responsive Element Binding Protein (CHRBP), a transcription factor that senses carbohydrate metabolites. CHRBP is conserved across species, expressed in key metabolic tissues (liver, kidney, small intestine, adipose tissue, pancreatic islets), and regulates genes involved in lipogenesis, glycolysis, and glucose production. Genetic variants in the MLXIPL locus (encoding CHRBP) are associated with cardio-metabolic risk factors in humans, underscoring its relevance to human health.

Discovery of CHRBP Isoforms and Their Implications

Over a decade ago, Dr. Herman's lab identified a novel isoform of CHRBP called CHRBP-beta, in addition to the canonical CHRBP-alpha. CHRBP-beta lacks the low glucose inhibitory domain present in CHRBP-alpha and is constitutively and potently active. This discovery provided a tool to assess overall CHRBP activity in human tissues. Studies showed higher CHRBP-beta expression in the livers of obese individuals and those with type 2 diabetes, suggesting its involvement in the pathogenesis of metabolic disease.

CHRBP and Fructose-Induced Metabolic Dysfunction: Unexpected Findings

Intrigued by an early observation from Kosaka Uea's lab (discoverer of CHRBP) that CHRBP knockout mice died rapidly on a high-fructose diet, Dr. Herman's lab sought to investigate CHRBP's role in fructose metabolism. They confirmed that fructose, unlike glucose, potently activates the expression of CHRBP beta and its target genes involved in glycolysis, lipogenesis, and fructose metabolism in the liver. This activation was shown to be dependent on CHRBP. Notably, fructose metabolism also enhances glucokinase activity in the liver by promoting its translocation to the cytoplasm, suggesting a mechanism by which fructose primes the liver for overall sugar metabolism.

However, when Dr. Herman's lab generated liver-specific CHRBP knockout mice, they found that these mice did not die on a high-fructose diet. Instead, they were protected against fructose-induced weight gain, steatosis, and hyperinsulinemia. This surprising result led them to investigate the role of CHRBP in other tissues, particularly the intestine, where significant first-pass fructose metabolism occurs.

The Crucial Role of Intestinal CHRBP in Fructose Tolerance

Further studies revealed that intestinal-specific CHRBP knockout mice exhibited profound intolerance to dietary fructose, characterized by intestinal distension and malabsorption. The underlying mechanism was identified as the CHRBP-dependent regulation of GLUT5, the primary fructose transporter in the intestine. In the absence of intestinal CHRBP, GLUT5 expression is severely reduced, impairing fructose absorption and leading to severe intestinal distress. These findings highlight a critical role for intestinal CHRBP in facilitating fructose absorption and preventing systemic overload.

Differential Susceptibility to Fructose Across Mouse Strains: The Role of Intestinal Handling

Dr. Herman then discussed the significant differences in susceptibility to fructose-induced metabolic disease across different inbred mouse strains. C3H/HeJ mice were found to be much more sensitive to high-fructose diets compared to C57BL/6J mice, exhibiting greater weight gain, hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis. Interestingly, C57 mice on a high-fructose diet even tended to lose weight. This differential sensitivity correlated with a more robust induction of CHRBP beta and its target genes in the livers of C3H mice.

Genetic intercrossing studies between these strains allowed the researchers to begin dissecting the complex fructose-induced phenotypes into distinct sub-phenotypes, revealing that body weight and liver triglyceride accumulation were strongly associated but independent of serum insulin and triglyceride levels. Recent work from Dr. Herman's lab suggests that the primary driver of these differences in susceptibility lies in the intestinal handling of fructose. Tracer studies showed significantly higher levels of fructose-1-phosphate in the livers of C3H mice compared to C57 mice after fructose gavage, indicating increased fructose reaching the liver in the sensitive strain. This suggests that variations in intestinal fructose absorption and metabolism, potentially influencing the amount of fructose delivered to the liver, are key determinants of fructose-induced metabolic disease susceptibility.

Future Directions

Dr. Herman concluded by emphasizing that the extent to which differences in intestinal dietary nutrient handling contribute to cardio-metabolic disease remains an understudied but critical area for future research. His lab aims to pursue these questions in collaboration with other investigators.

Discussion Points

The subsequent question-and-answer session provided further insights:

• Dr. Bage discussed how elevated free fatty acid levels in patients with diabetes further impair splanchnic glucose uptake, potentially by affecting hepatic glucokinase activity, highlighting a complex interplay between glucose and lipid metabolism. Dr. Herman noted that fructose metabolism can also impact glucokinase availability chronically, potentially contributing to this phenomenon. He also mentioned that fatty acids might enhance endogenous fructose synthesis.
• Dr. Ying inquired about similar genetic variations in MLXIPL or other relevant genes in human populations that might explain individual differences in response to fructose. Dr. Herman confirmed that genetic variants in the CHRBP locus are indeed associated with various metabolic phenotypes in humans, and population genetic studies suggest interactions between sugar ingestion, CHRBP variants, and cardio-metabolic traits. This suggests the potential for these genetic factors to serve as biomarkers for therapeutic purposes, although the complexity requires further investigation.
• A question was raised regarding the link between fructose and gout, given that fructose does not contain nitrogen, the source of uric acid. Dr. Herman acknowledged that the precise mechanism is not fully understood but suggested that CHRBP might regulate nucleotide turnover, and increased purine catabolism as a consequence could lead to elevated uric acid levels in humans who lack uricase.
• The historical consumption of fruit, which contains fructose, was discussed. Dr. Herman explained that the key difference lies in the amount and rate of fructose absorption. The lower sugar content and the presence of fiber and other components in fruit lead to slower and reduced fructose delivery to the liver compared to rapidly absorbed sugars in SSBs, potentially explaining the differential health effects.

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