Could the way we metabolize fructose be a key driver of fatty liver? Human trials are giving researchers a stronger reason to ask. Studies have approached the question from two directions: reducing sugar exposure and blocking KHK, the enzyme that starts fructose metabolism. Both approaches have reduced liver fat in selected groups. Together, these findings support a possibility worth taking seriously: this pathway may play an active role in the buildup of liver fat.

Fructose is part of table sugar and many sweetened drinks. It is also present in whole fruit, where the food and usual serving differ from a large sugary drink. KHK helps start fructose metabolism. That pathway can affect the liver's energy state and the materials available for making fat. How much it contributes in people is the question these studies begin to test.

What does the human evidence show?

There are two useful kinds of human evidence here: changing what people consume and changing the KHK pathway directly. They answer related but different questions.

In a six-month randomized study of 47 adults with overweight, participants were assigned one liter a day of sucrose-sweetened cola, milk with similar calories, diet cola or water. MRI spectroscopy found a greater rise in liver fat in the regular-cola group than in the other drink groups. Total body fat did not differ significantly across groups. That is a reason to take repeated large sweetened-drink exposure seriously; it is not evidence that an occasional piece of fruit has the same effect. The drink contained sucrose, which combines fructose and glucose, so the study cannot isolate fructose alone.

A second randomized study enrolled 40 adolescent boys who already had fatty liver disease. Families in the intervention group received food designed to keep free sugars below 3% of calories for eight weeks. MRI-measured liver fat fell more than with usual diet: from 25% to 17% on average, compared with 21% to 20% in the usual-diet group. “Free sugars” includes added sugars and sugars in fruit juice. The study changed a whole diet and studied a narrow group, so it does not identify one molecule as the sole cause or prove a long-term clinical outcome.

The double-blind adult FRUITLESS trial tested a more focused question. Forty-four adults with overweight and a high fatty-liver index were randomized to a six-week fructose-restricted diet while taking either glucose or equal-calorie fructose supplements three times daily. Thirty-seven completed the study. Liver fat fell in both groups, but the glucose group had an additional 0.7-percentage-point reduction relative to the fructose group. The trial found no significant between-group differences in glucose tolerance or serum lipids. The result supports a small, measurable effect of fructose substitution in this setting.

These diet trials show that sugar exposure can move liver fat in people. Their different designs also help distinguish a broad dietary change from a more focused fructose substitution.

Why KHK matters to the liver

KHK adds a phosphate group to fructose, producing fructose-1-phosphate. This first step uses ATP, the cell's immediate energy currency. When fructose arrives quickly, the pathway can briefly draw down ATP and phosphate, while downstream metabolism can feed fat synthesis and uric-acid production. That is a mechanistic reason the form and amount of sugar may matter, beyond a simple calorie count. It does not mean that every gram of fructose becomes liver fat.

The pathway is also testable in people. In a 16-week randomized trial of 164 adults with fatty liver and type 2 diabetes, researchers tested the pharmaceutical KHK inhibitor PF-06835919. The higher dose reduced MRI-measured whole-liver fat relative to placebo. The study's HbA1c endpoint did not improve significantly. That combination is informative: KHK is biologically consequential in this selected human setting, yet a liver-fat marker is not the same as a proven long-term treatment benefit.

A newer 2026 crossover trial studied 15 adults with MASLD for six weeks on the same experimental KHK inhibitor and six weeks on placebo. The drug reduced liver fat and improved hepatic insulin sensitivity without changing body weight. That raises the possibility of improving liver health without first requiring weight loss. Larger, longer studies are needed to learn how durable and clinically meaningful these changes are.

For a broader explanation of the pathway, read our fructose and metabolic health guide. Our KHK research update follows the experimental drug work in more detail.

How important could this pathway be?

The human studies give researchers a practical way to test fructose metabolism in fatty liver. The next questions are how much this pathway contributes in different people, who benefits most when it is changed, and whether the improvements last. Total dietary pattern, energy balance, insulin resistance, genetics, alcohol exposure and other conditions also shape liver health.

The newer term metabolic dysfunction-associated steatotic liver disease (MASLD) is often used where older studies say nonalcoholic fatty liver disease (NAFLD); the name reflects that wider context. Liver fat can be present without obvious symptoms, so individual risk and follow-up call for appropriate clinical assessment rather than a self-test.

Where does luteolin fit?

Luteolin is a plant compound studied as a KHK inhibitor. In laboratory work and a mouse kidney-injury model, researchers found KHK-inhibiting activity. The mouse treatment was given intravenously. Those experiments did not show that swallowing luteolin lowers liver fat in people. Oral exposure also changes the compound: a human absorption study measured circulating luteolin metabolites, not human KHK inhibition or liver outcomes.

This distinction matters because the successful liver-fat trial used a purpose-built pharmaceutical KHK inhibitor, not luteolin. The next useful experiment for luteolin would measure whether a defined oral formulation changes KHK-related biology in humans at a feasible exposure, before asking whether it changes liver outcomes. Our luteolin and KHK evidence explainer lays out that laboratory work.

What should a reader take away?

Fructose metabolism may play a key role in fatty liver. The evidence now includes human interventions that change liver fat, giving researchers a practical way to test that possibility. The opportunity ahead is to establish who benefits, how large the benefit can be, and whether it lasts.

For readers, the studies offer a reason to notice repeated exposure to sweetened drinks and other concentrated free sugars. If you are concerned about liver health, discuss appropriate testing and changes with a qualified clinician; body shape or symptoms are not a substitute for assessment.

Written by Chris Mearns, founder of LIV3 Health. LIV3 develops and sells SugarShield, which contains luteolin. The cited liver-fat trials did not test SugarShield as a finished product. This article is educational and is not medical advice; individual diagnosis and treatment decisions belong with a qualified clinician.

References

1. Maersk M, et al. Sucrose-sweetened beverages and ectopic fat: randomized study. American Journal of Clinical Nutrition, 2012.
2. Schwimmer JB, et al. Low free sugar diet and liver fat in adolescent boys: randomized trial. JAMA, 2019.
3. Simons N, et al. FRUITLESS: isocaloric fructose restriction and intrahepatic lipid. American Journal of Clinical Nutrition, 2021.
4. Saxena AR, et al. PF-06835919 in adults with NAFLD and type 2 diabetes: randomized phase 2a trial. Diabetes, Obesity and Metabolism, 2023.
5. Koene EJC, et al. PF-06835919 in 15 adults with MASLD: randomized crossover trial. Nature Metabolism, 2026.
6. Andres-Hernando A, et al. Fructokinase blockade in experimental kidney injury. Nature Communications, 2017.
7. Hayasaka N, et al. Oral luteolin absorption and metabolism in humans. Journal of Agricultural and Food Chemistry, 2018.