Hormonal
Chronic high-fructose consumption promotes hepatic de novo lipogenesis (DNL) and intrahepatic lipid accumulation primarily by bypassing rate-limiting glycolytic steps and activating transcription factors ChREBP and SREBP1c, leading to increased VLDL secretion and dyslipidemia.
Fructose metabolism uniquely stimulates liver fat production through specific biological pathways (ChREBP/SREBP1c). However, human studies show that if you replace other calories with fructose without gaining weight (isocaloric), your liver fat may not increase more than if you ate those other calories. The real danger of fructose is that it contributes to excess calorie intake and weight gain. Focus on total caloric balance first; reducing high-fructose corn syrup and added sugars is a smart move for weight management, but don't assume fructose alone causes fatty liver if you are in a caloric deficit.
Mechanistically, hepatic fructose metabolism yields precursors that can be used for gluconeogenesis and de novo lipogenesis (DNL). Fructose-derived precursors also act as nutritional regulators of the transcription factors, including ChREBP and SREBP1c, that regulate the expression of hepatic gluconeogenesis and DNL genes. In support of these mechanisms, fructose intake increases hepatic gluconeogenesis and DNL and raises plasma glucose and triglyceride levels in humans.
Why this rating
Strong mechanistic evidence from tracer studies and animal models; human clinical evidence for liver fat accumulation is mixed/inconclusive.
Source
Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease
Kasper W. ter Horst et al. · Nutrients · 2017
DOI 10.3390/nu9090981
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