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.
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