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Background <p>Dietary fatty acids are involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). We examined the mechanism by which dietary fatty acid composition affects MASLD pathogenesis.</p> Methods <p>The MASLD mouse model was developed by feeding a high-fat diet (HFD) rich in palmitic acid (PA), trans-fatty acids (TFAs), or oleic acid (OA). For in vitro experiments, Hepa 1–6 cells were exposed to PA, elaidic acid (a representative TFA), and OA. Glycerol-3-phosphate acyltransferase 1 (GPAM) expression in Hepa 1–6 cells was manipulated using a plasmid encoding GPAM and GPAM-specific siRNAs. In addition, GPAM depletion in the liver of HFD-fed mice was achieved using a pH-sensitive multifunctional envelope-type nanodevice as a siRNA carrier. Liver specimens from patients with MASLD were also analyzed.</p> Results <p>The TFA group displayed higher serum alanine–aminotransferase and hepatic triglyceride content but lower serum fasting triglyceride and visceral adipose tissue (VAT) compared with that in the PA and OA groups. Hepatic GPAM expression in the TFA group was higher than in the PA group. Consistently, TFA-treated Hepa 1–6 cells showed a greater GPAM increase than that with OA and PA. GPAM-overexpressing Hepa 1–6 cells showed increased triglyceride accumulation, whereas GPAM-deficient cells failed to accumulate triglyceride. Hepatic GPAM knockdown in HFD-fed mice suppressed steatosis and increased VAT. Notably, hepatic GPAM gene expression was higher in patients with severe steatosis than in those with non-severe steatosis.</p> Conclusions <p>A TFA-rich HFD increased hepatic GPAM expression, exacerbated steatosis, and decreased VAT. Therefore, GPAM may regulate systemic fat accumulation in the body.</p>

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GPAM upregulation enhances hepatic fat deposition and reduces visceral adipose tissue in response to trans-fatty acids

  • 期刊论文

  • 发表日期：

    2025年10月4日

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  • Teruki Miyake,
  • Osamu Yoshida,
  • Shinya Furukawa,
  • Yusuke Sato,
  • Yoshimasa Murakami,
  • Ayumi Kanamoto,
  • Masumi Miyazaki,
  • Akihito Shiomi,
  • Hironobu Nakaguchi,
  • Mitsuhito Koizumi,
  • Takao Watanabe,
  • Yoshio Tokumoto,
  • Masashi Hirooka,
  • Masanori Abe,
  • Bunzo Matsuura,
  • Yoichi Hiasa

摘要

Background

Dietary fatty acids are involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). We examined the mechanism by which dietary fatty acid composition affects MASLD pathogenesis.

Methods

The MASLD mouse model was developed by feeding a high-fat diet (HFD) rich in palmitic acid (PA), trans-fatty acids (TFAs), or oleic acid (OA). For in vitro experiments, Hepa 1–6 cells were exposed to PA, elaidic acid (a representative TFA), and OA. Glycerol-3-phosphate acyltransferase 1 (GPAM) expression in Hepa 1–6 cells was manipulated using a plasmid encoding GPAM and GPAM-specific siRNAs. In addition, GPAM depletion in the liver of HFD-fed mice was achieved using a pH-sensitive multifunctional envelope-type nanodevice as a siRNA carrier. Liver specimens from patients with MASLD were also analyzed.

Results

The TFA group displayed higher serum alanine–aminotransferase and hepatic triglyceride content but lower serum fasting triglyceride and visceral adipose tissue (VAT) compared with that in the PA and OA groups. Hepatic GPAM expression in the TFA group was higher than in the PA group. Consistently, TFA-treated Hepa 1–6 cells showed a greater GPAM increase than that with OA and PA. GPAM-overexpressing Hepa 1–6 cells showed increased triglyceride accumulation, whereas GPAM-deficient cells failed to accumulate triglyceride. Hepatic GPAM knockdown in HFD-fed mice suppressed steatosis and increased VAT. Notably, hepatic GPAM gene expression was higher in patients with severe steatosis than in those with non-severe steatosis.

Conclusions

A TFA-rich HFD increased hepatic GPAM expression, exacerbated steatosis, and decreased VAT. Therefore, GPAM may regulate systemic fat accumulation in the body.