Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate

Abstract

Fructose consumption has risen dramatically in recent decades due to use of sucrose and high fructose corn syrup in beverages and processed foods 1 , contributing to rising rates of obesity and non-alcoholic fatty liver disease (NAFLD) 2 – 4 . Fructose intake triggers hepatic de novo lipogenesis (DNL) 4 – 6 , which is initiated from acetyl-CoA. ATP-citrate lyase (ACLY) cleaves cytosolic citrate to generate acetyl-CoA and is upregulated upon carbohydrate consumption 7 . Ongoing clinical trials are pursuing ACLY inhibition for treatment of metabolic diseases 8 . Nevertheless, the route from dietary fructose to hepatic acetyl-CoA and lipids remains unproven. Here we show, using in vivo isotope tracing, that liver-specific deletion of Acly fails to suppress fructose-induced DNL in mice. Dietary fructose is converted by the gut microbiome into acetate 9 , which supplies lipogenic acetyl-CoA independently of ACLY 10 . Depletion of the microbiome or silencing of hepatic ACSS2, which generates acetyl-CoA from acetate, potently suppresses conversion of a fructose bolus into hepatic acetyl-CoA and fatty acids, bypassing ACLY. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage and microbial acetate contribute to lipogenesis. The DNL transcriptional program, on the other hand, is activated in response to fructose in a manner independent of acetyl-CoA metabolism. These data reveal a two-pronged mechanism regulating hepatic DNL, in which fructolysis within hepatocytes provides a signal to promote DNL gene expression, while microbial acetate generation feeds lipogenic acetyl-CoA pools.

Can You Trust Your Gut? Implicating a Disrupted Intestinal Microbiome in the Progression of NAFLD/NASH

“…In their recent paper, Zhao et al set out to tease apart the relative contribution of these two pathways in fructose consumption-mediated increases in hepatic DNL (45). Counter to current dogma surrounding the role of dietary fructose in hepatic steatosis, Zhao et al demonstrated that dietary fructose is converted to acetate by the gut microbiome, and can be used by the liver as a precursor for DNL (45). Prior to these data, it was believed that once in the hepatocyte, fructose enters the tricarboxylic acid (TCA) cycle and is converted to citrate.…”

Sex Differences in Dietary Copper-Fructose Interaction-Induced Alterations of Gut Microbial Activity are Not Correlated to Hepatic Steatosis

“…One part is gut bacteria derived acetate which serves as a substrate for acetyl-CoA synthesis via acyl-CoA synthetase short chain family member 2 (ACSS2) in the liver. Second, fructose metabolism in hepatocytes activates a signal leading to lipogenic gene expression (64).…”

Inflammation in Primary and Metastatic Liver Tumorigenesis–Under the Influence of Alcohol and High-Fat Diets

“…Insulin resistance, which is a consequence of obesity, contributes to increased levels of circulating FFAs by suppressing lipolysis, and this source represents 59% of all FFAs found in the liver of NAFLD patients [64,65]. Excess fructose intake, which is common in Western diets, strongly upregulates DNL and accounts for approximately 26% of FFAs in the liver [64,66,67]. In a choline deficient-high fat diet (CD-HFD) mouse model of NASH, activation of CD8 + T cells and NKT cells induced FFA uptake by hepatocytes via the lymphotoxin-β receptor and accelerated NASH to HCC transition by activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling in hepatocytes [68].…”

“…In recent study, bacterial metabolism of dietary fructose, obtained from fruits and increasingly from processed foods enriched in high-fructose corn syrup, was shown to enhance DNL. In a dual mechanism, dietary fructose promoted transcriptional up-regulation of DNL genes, while bacterial metabolism of excess fructose into the short-chain fatty acid acetate in the intestine, provided a source of acetyl-CoA in hepatocytes to feed DNL [67].…”