Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance

Related Experiment Video

Updated: Jan 10, 2026

Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
06:26

Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis

Published on: July 18, 2025

660

Rongya Tao1, Oliver Stöhr1, Ozlem Tok2

  • 1Division of Endocrinology Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Nature Communications
|November 23, 2025
PubMed

Insights

Metabolic-associated steatotic liver disease (MASLD) can develop without insulin resistance, driven by fructose metabolism. Follistatin (FST) promotes MASLD by increasing hepatic fat accumulation, even without insulin signaling.

Area of Science:

  • Hepatology
  • Metabolic Syndrome
  • Endocrinology

Background:

  • Metabolic-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are linked to hepatic insulin resistance (IR) and type 2 diabetes (T2D).
  • Hepatic lipogenesis stimulated by insulin is traditionally considered crucial for MASLD development.

Purpose of the Study:

  • To investigate the role of fructose metabolism and insulin signaling in MASLD pathogenesis.
  • To challenge the established notion that insulin-stimulated hepatic lipogenesis is essential for MASLD development.

Main Methods:

  • Utilized male liver-direct knockout (LDKO) mice lacking hepatic insulin receptor substrates.
  • Administered fructose-enriched diets (MASH diet/GAN or high-fructose diet).
  • Traced hepatic triacylglyceride synthesis using [U-13C]fructose and assessed the impact of Follistatin (Fst) manipulation on MASLD development.

Main Results:

  • LDKO mice developed acute MASLD when fed fructose-enriched diets, despite complete hepatic IR.
  • Fructose enhanced hepatic re-esterification of circulating fatty acids in LDKO mice.
  • Inactivating hepatic Fst prevented MASLD in LDKO mice, while Fst overexpression accelerated MASLD/MASH in wild-type mice.
  • Elevated serum FST levels correlated with increased adipose IR and hepatic triacylglyceride accumulation in human study participants.

Conclusions:

  • Insulin-stimulated hepatic lipogenesis is not essential for MASLD development.
  • Fructose metabolism plays a critical role in promoting MASLD, particularly in the context of hepatic insulin resistance.
  • Follistatin (FST) acts as a key mediator in MASLD pathogenesis by potentiating hepatic fat accumulation.

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