Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression

Sekiya, Motohiro; Yahagi, Naoya; Matsuzaka, Takashi; Najima, Yuho; Nakakuki, Masanori; Nagai, Ryozo; Ishibashi, Shun; Osuga, Jun-ichi; Yamada, Nobuhiro; Shimano, Hitoshi

doi:10.1016/j.hep.2003.09.028

Cited by 415Liver Disease Diagnosis and TreatmentFatty Acid Research and HealthPeroxisome Proliferator-Activated Receptors

Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression

Sekiya, Motohiro, Yahagi, Naoya, Matsuzaka, Takashi, Najima, Yuho, Nakakuki, Masanori, Nagai, Ryozo, Ishibashi, Shun, Osuga, Jun-ichi +2 more·2003·Hepatology

DOI 10.1016/j.hep.2003.09.028

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Abstract

Leptin-deficient ob/ob mice show many characteristics of obesity, including excess peripheral adiposity as well as severe hepatic steatosis, at least in part, due to increased hepatic lipogenesis. Polyunsaturated fatty acids (PUFAs) are not only ligands for peroxisome proliferator-activated receptor (PPAR) alpha but are also negative regulators of hepatic lipogenesis, which is thought to be mediated by the repression of sterol regulatory element-binding protein (SREBP)-1. We have previously shown that the disruption of SREBP-1 in ob/ob mice decreased their liver triglyceride storage. To examine whether PUFAs could reduce hepatic triglyceride deposition, we challenged ob/ob mice with dietary PUFA. It is demonstrated that PUFA markedly decreased the mature form of SREBP-1 protein and thereby reduced the expression of lipogenic genes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1) in the livers of ob/ob mice. Consequently, the liver triglyceride content and plasma alanine aminotransferase (ALT) levels were decreased. Furthermore, both hyperglycemia and hyperinsulinemia in ob/ob mice were improved by PUFA administration, similar to the effect of PPARalpha activators. In conclusion, PUFAs ameliorate obesity-associated symptoms, such as hepatic steatosis and insulin resistance, presumably through both down-regulation of SREBP-1 and activation of PPARalpha.

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The mechanistic underpinnings of these fatty acid effects involve downregulation of SREBP-1c and activation of PPARα.
“The mechanistic underpinnings involve the downregulation of SREBP-1c and activation of PPARα (98).”
From Diet and physical exercise as key players to tackle MASLD through improvement of insulin resistance and metabolic flexibility (2024) · cites this paper as [98]
These fatty acids have demonstrated efficacy in enhancing insulin sensitivity, ameliorating steatohepatitis, and reducing intrahepatic triglyceride content.
“Moreover, these fatty acids have demonstrated efficacy in enhancing insulin sensitivity, ameliorating steatohepatitis, and reducing intrahepatic triglyceride content.”
From Diet and physical exercise as key players to tackle MASLD through improvement of insulin resistance and metabolic flexibility (2024) · cites this paper as [98]

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Authors: Sekiya, M., Yahagi, N., Matsuzaka, T., Najima, Y., Nakakuki, M., Nagai, R., Ishibashi, S., Osuga, J.-I., Yamada, N., & Shimano, H.
Affiliations: The University of Tokyo (JP)
University of Tsukuba (JP)
Corresponding author: Shimano, Hitoshi
ORCID: Sekiya, Motohiro
Yahagi, Naoya
Matsuzaka, Takashi
Najima, Yuho
Nagai, Ryozo
Ishibashi, Shun
Shimano, Hitoshi
Venue: Hepatology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2003-12
Volume: 38
Issue: 6
Pages: 1529-1539
ISSN: 0270-9139 (ISSN-L)
DOI: 10.1016/j.hep.2003.09.028
OpenAlex: W2079378050
Cited by: 415
References: 39
Citations by year: 2026: 2 · 2025: 4 · 2024: 12 · 2023: 21 · 2022: 12 · 2021: 17 · 2020: 24 · 2019: 12 · 2018: 16 · 2017: 21 · 2016: 23 · 2015: 25 · 2014: 19 · 2013: 34 · 2012: 17
FWCI: 9.29
Type: journal article
Language: en
Open access: closed
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 4292 d)
Locations: Hepatology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: polyunsaturated fatty acids, hepatic steatosis, SREBP1, PPARα, leptin-deficient ob/ob mice, hepatic lipogenesis, fatty acid synthase, stearoyl-CoA desaturase 1, insulin resistance, hyperinsulinemia, hyperglycemia, obesity
MeSH terms: Alanine Transaminase, Animals, Cholesterol, DNA-Binding Proteins, Fatty Acids, Unsaturated, Fatty Liver, Gene Expression Regulation, Insulin Resistance, Liver, Mice, Inbred C57BL, Mice, Obese, Transcription Factors, Triglycerides, Receptors, Cytoplasmic and Nuclear, CCAAT-Enhancer-Binding Proteins, Mice, Sterol Regulatory Element Binding Protein 1

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Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression

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