Cited by 162Fatty Acid Research and HealthLipid metabolism and biosynthesisCholesterol and Lipid Metabolism

Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways

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Botolin, Daniela, Wang, Yun, Christian, Barbara, Jump, Donald B.·2006·Journal of Lipid Research

Abstract

Insulin induces and dietary n-3 PUFAs suppress hepatic de novo lipogenesis by controlling sterol-regulatory element binding protein-1 nuclear abundance (nSREBP-1). Our goal was to define the mechanisms involved in this regulatory process. Insulin treatment of rat primary hepatocytes rapidly augments nSREBP-1 and mRNA(SREBP-1c) while suppressing mRNA(Insig-2) but not mRNA(Insig-1). These events are preceded by rapid but transient increases in Akt and Erk phosphorylation. Removal of insulin from hepatocytes leads to a rapid decline in nSREBP-1 [half-time (T1/2) approximately 10 h] that is abrogated by inhibitors of 26S proteasomal degradation. 22:6,n-3, the major n-3 PUFA accumulating in livers of fish oil-fed rats, suppresses hepatocyte levels of nSREBP-1, mRNA(SREBP-1c), and mRNA(Insig-2) but modestly and transiently induces mRNA(Insig-1). More importantly, 22:6,n-3 accelerates the disappearance of hepatocyte nSREBP-1 (T1/2 approximately 4 h) through a 26S proteasome-dependent process. 22:6,n-3 has minimal effects on microsomal SREBP-1 and sterol-regulatory element binding protein cleavage-activating protein or nuclear SREBP-2. 22:6,n-3 transiently inhibits insulin-induced Akt phosphorylation but induces Erk phosphorylation. Inhibitors of Erk phosphorylation, but not overexpressed constitutively active Akt, rapidly attenuate 22:6,n-3 suppression of nSREBP-1. Thus, 22:6,n-3 suppresses hepatocyte nSREBP-1 through 26S proteasome- and Erk-dependent pathways. These studies reveal a novel mechanism for n-3 PUFA regulation of hepatocyte nSREBP-1 and lipid metabolism.

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  • n-3 PUFAs suppress de novo lipogenesis by inhibiting SREBP-1 expression and maturation and reducing ChREBP activity, thereby curbing hepatic glycolysis and lipid synthesis.

    “Beyond enhancing β-oxidation, n-3 PUFAs concurrently suppress de novo lipogenesis by inhibiting the expression and maturation of SREBP-1, and by reducing the activity of ChREBP, thereby curbing hepatic glycolysis and lipid synthesis.34–37”

    From The Impact of Omega-3 Fatty Acids on Triglyceride Levels in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-Analysis of Randomized Controlled Trials with Subgroup Analysis by Diabetes Status (2026) · cites this paper as [34]

    The Abstract (page not supplied) says PUFAs suppress de novo lipogenesis through reduced nuclear SREBP-1 and describes inhibition of SREBP-1 expression and proteolytic processing as reported mechanisms. This study specifically finds that DHA accelerates degradation of nuclear SREBP-1, with little effect on microsomal SREBP-1. The cited paper does not establish reduced ChREBP activity or curtailed hepatic glycolysis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • Omega-3 fatty acids lead to intracellular degradation of apo B, thereby diminishing VLDL assembly and decreasing VLDL secretion.

    “In addition, n-3 FAs lead to intracellular degradation of apo B, which may be a result of decreased triglyceride availability or autophagic destruction of apo B via post-Golgi oxidation, 90 thereby diminishing the assembly of VLDL particles in the hepatocyte and decreasing VLDL secretion.91,92”

    From Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association (2019) · cites this paper as [90]

    The Discussion reports that DHA accelerates degradation of nuclear SREBP-1 in rat hepatocytes, not apo B. Searches of our copy for apo B, VLDL assembly and VLDL secretion found no passage addressing the attributed mechanism or its proposed outcome. (LLM, conf=0.75)

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Authors
Botolin, D., Wang, Y., Christian, B., & Jump, D. B.
Affiliations
Michigan State University (US)
Venue
Journal of Lipid Research
Publisher
Elsevier BV
Published
2006-01
Volume
47
Issue
1
Pages
181-192
ISSN
0022-2275 (ISSN-L)
OpenAlex
W2164098551
Cited by
162
References
40
Citations by year
2026: 2 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 8 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 6 · 2015: 6 · 2014: 5 · 2013: 8 · 2012: 10
FWCI
11.92
Type
journal article
Language
en
Open access
Locations
  • Journal of Lipid Research (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Agriculture
  • National Institutes of Health
  • Cooperative State Research, Education, and Extension Service
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK043220)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
docosahexaenoic acid, omega-3 fatty acids, SREBP1, INSIG2, INSIG1, 26S proteasome, ERK1/2 phosphorylation, Akt phosphorylation, insulin signaling, hepatocytes, hepatic de novo lipogenesis, SREBP-1c, SREBP2, lipid metabolism
MeSH terms
Animals, Base Sequence, Cell Nucleus, Dietary Fats, Docosahexaenoic Acids, Insulin, Male, Membrane Proteins, Protease Inhibitors, RNA, Messenger, Rats, Sprague-Dawley, MAP Kinase Signaling System, Hepatocytes, Proteasome Endopeptidase Complex, Intracellular Signaling Peptides and Proteins, Lipid Metabolism, Rats, Sterol Regulatory Element Binding Protein 1, Proteasome Inhibitors

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