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Hepatocyte SLCO4C1 is a cAMP uptake transporter for inhibiting lipogenesis and a therapeutic target for MASLD

Xiaojia Huang1, Sen Liang1, Nan Zhao1

  • 1Department of Gastroenterology, Institute of Digestive Diseases of PLA, Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Medical Research Center, Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China.

Nature Communications
|March 14, 2026
PubMed

Insights

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves upregulated SLCO4C1, a cAMP transporter that suppresses fat buildup. Enhancing SLCO4C1 activity shows promise for treating MASLD.

Area of Science:

  • Hepatology and Metabolic Research
  • Molecular Biology
  • Biochemistry

Background:

  • Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern lacking targeted therapies.
  • SLCO4C1, a transporter, has an uncharacterized role in liver disease pathogenesis.
  • Understanding MASLD mechanisms is crucial for developing precision medicine.

Purpose of the Study:

  • To investigate the role of SLCO4C1 in MASLD pathogenesis.
  • To elucidate the molecular mechanisms by which SLCO4C1 influences liver steatosis.
  • To explore the therapeutic potential of targeting the SLCO4C1-cAMP axis in MASLD.

Main Methods:

  • Utilized human, mouse, and cellular models of MASLD.
  • Investigated SLCO4C1 expression and function in hepatocytes.
  • Employed AAV8-TBG for hepatocyte-specific Slco4c1 delivery in mice.
  • Administered forskolin to assess cAMP-mediated effects.

Main Results:

  • Hepatocyte SLCO4C1 is upregulated in MASLD and transports cAMP, suppressing lipogenesis via the PKA-CREB-SREBP1 pathway.
  • Hepatocyte-specific Slco4c1 delivery ameliorated steatosis, inflammation, and fibrosis in MASLD mice.
  • Elevating intrahepatic cAMP levels, via Slco4c1 or forskolin, alleviated MASLD progression.
  • FGF21 upregulates hepatic Slco4c1 via ERK/MAPK and EGR1 signaling, increasing cAMP.

Conclusions:

  • SLCO4C1 acts as a critical cAMP transporter in hepatocytes, suppressing lipogenesis and mitigating MASLD progression.
  • Targeting the SLCO4C1-cAMP signaling axis presents a promising therapeutic strategy for MASLD.
  • The FGF21-ERK/MAPK-EGR1-SLCO4C1 pathway regulates intrahepatic cAMP levels in MASLD.

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