Fructose metabolism is key to development of metabolic disease

Presenters: Kathryn E. Wellen, PhD, Cholsoon Jang, PhD, Michael Karin, MD, and Mark A. Herman, MD

Fructose consumption has been increasing over the past several decades and has been linked to increasing rates of several metabolic diseases in addition to hepatocellular carcinoma (HCC). Fructose metabolism was the focus of a symposium in which four presenters summarized the current knowledge with respect to the role of excess fructose consumption in metabolic disease.

Specifically, dietary fructose is a major promoter of hepatic de novo lipogenesis, in which carbon precursors of acetyl-CoA are converted into fatty acids, contributing to fatty liver, said Kathryn E. Wellen, PhD, associate professor of cancer biology, University of Pennsylvania, Philadelphia.

The ATP citrate lyase (ACLY) enzyme cleaves cytosolic citrate to generate acetyl-CoA. Dietary fructose is converted to acetate by the gut microbiota, which reaches the liver by the portal vein. When consumed gradually to facilitate absorption in the small intestine, fructose increases de novo lipogenesis by both citrate cleavage in hepatocytes and gut microorganism-derived acetate. Multiple sources (ie, fructolysis within hepatocytes, microbial acetate generation) can contribute to lipogenic acetyl-CoA pools. Suppression of both ACLY and acetate use is required to suppress de novo lipogenesis during gradual fructose consumption; this observation may lead to new therapeutic interventions for treatment of metabolic diseases, said Dr. Wellen.¹

Fructose studies have been highly “liver-centric” with good reason, said Cholsoon Jang, PhD, assistant professor of biological chemistry, University of California, Irvine. Ketohexokinase (KHK), an essential enzyme for fructose catabolism, is highly expressed in the liver “so it makes sense to study liver fructose metabolism,” he said.

KHK-knockout mice do not develop fatty liver despite fructose consumption, which can likely be explained by the induction of the de novo lipogenesis transcriptional program in the liver being independent of both ACLY and the microbiome.

The small intestine clears most low-dose fructose before fructose reaches the liver, but high-dose fructose overwhelms intestinal catabolism and spills over to the liver where it is converted to fat.² Intestinal fructose catabolism shields the liver from steatosis.³ Slow fructose intake can suppress fructose-induced hepatic lipogenesis. “To prevent fructose-induced fatty liver, [we] suggest you ought to take fructose as slowly as possible to give sufficient time for intestine to catabolize fructose,” said Dr. Jang.

In his presentation, Michael Karin, MD, professor of pharmacology, University of California, San Diego, focused on the link between fructose and tissue injury in nonalcoholic fatty liver disease.

Mice fed high-fructose diets show a much higher HCC tumor burden at 12 months compared with their glucose-fed littermates. As expected, a high-fructose diet stimulated de novo lipogenesis, but it also led to marked induction of lipogenic genes and enzymes and inflammatory cytokines, he said. Prolonged high-fructose diet consumption causes intestinal epithelial barrier disruption through bacterial dysbiosis and downregulation of tight junction genes.⁴

A fructose-rich drink also induces hepatosteatosis, expression of liver inflammatory genes, and expression of lipogenic genes, and leads to a further decrease in barrier permeability. This effect is absent with a glucose drink, said Dr. Karin.

“The reason we looked at the intestine is that the intestine and the liver are connected via the portal circulation (gut-liver axis),” he said. “Therefore, what happens in the intestine, including barrier disruption and epithelial erosion, has a profound impact on the liver.” Restoring barrier integrity with chemical chaperones can reverse fructose-induced endoplasmic reticulum stress in intestinal epithelial cells.

He showed data demonstrating that a high-fructose diet can lead to nonalcoholic steatohepatitis and HCC development via intestinal epithelial barrier disruption and tumor necrosis factor (TNF) induction; TNF signaling in hepatocytes leads to Caspase-2 induction, eventually leading to conversion of acetyl-CoA to fatty acids.

By inducing antimicrobial proteins (eg, Reg3), interleukin (IL)-22 is a critical regulator of intestinal homeostasis. A high-fat diet as well induces intestinal ER stress and barrier defects, both of which are reversed by IL-22.⁵ IL-22 therapy therefore may promote regeneration, healing, and reversal of dysbiosis, said Dr. Karin. As evidence, he pointed to IL-22 reversal of hepatosteatosis in mice fed high-fructose diets.

Fructose consumption activates hepatic ChREBP, a transcription factor that regulates hepatic metabolic gene expression programs, Mark A. Herman, MD, said in his presentation on the challenge of excess fructose consumption. ChREBP stimulates glucose-6 phosphatase expression to drive glucose production, and this action is dominant over insulin’s ability to suppress glucose.⁶

Fructose consumption activates intestinal and hepatic ChREBP, which mediates adaptive and maladaptive metabolic responses. Hepatic ChREBP is essential for fructose-induced metabolic disease, and intestinal ChREBP is essential for fructose absorption and fructose tolerance,⁷ said Dr. Herman, associate professor of medicine, Duke University, Durham, N.C.

Main menu

User menu

Search

Fructose metabolism is key to development of metabolic disease

Navigate

Authors & Reviewers