Diet-induced RKIP downregulation disrupts PC/PE-ER homeostasis to drive MASLD

Area of Science:

• Biochemistry
• Molecular Biology
• Hepatology

Background:

• High-fat diet (HFD) is a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD).
• The precise molecular mechanisms linking dietary fat intake to liver dysfunction in MASLD are not fully understood.
• Understanding these pathways is critical for developing effective therapeutic strategies.

Purpose of the Study:

• To elucidate the role of Raf kinase inhibitory protein (RKIP) in the pathogenesis of diet-induced MASLD.
• To investigate the molecular mechanisms by which RKIP influences hepatic lipid metabolism and endoplasmic reticulum (ER) homeostasis.
• To identify RKIP as a potential therapeutic target for MASLD prevention.

Main Methods:

• Analysis of RKIP expression in MASLD patients and HFD-fed male mice.
• Investigation of RKIP regulation by fatty acid uptake and S-palmitoylation.
• Assessment of RKIP's role in PEMT translation via m6A RNA binding.
• Examination of the effects of hepatocyte-specific RKIP depletion on liver steatosis and ER stress.

Main Results:

• Hepatic RKIP is downregulated in MASLD patients and HFD-fed male mice.
• Fatty acid uptake inhibits RKIP S-palmitoylation, leading to its ER-associated degradation.
• RKIP facilitates YTHDF1 binding to m6A-modified PEMT mRNA, promoting PEMT translation.
• RKIP depletion exacerbates PC/PE imbalance and ER stress, worsening MASLD.
• RKIP protein levels positively correlate with PEMT but inversely with MASLD severity.

Conclusions:

• RKIP downregulation is a key cellular mechanism in diet-induced MASLD, driven by HFD and fatty acid uptake.
• The HFD-RKIP-PEMT pathway critically regulates hepatic ER homeostasis and lipid metabolism.
• RKIP represents a promising therapeutic target for preventing and treating MASLD.