Hepatic Insulin Resistance Is Sufficient to Produce Dyslipidemia and Susceptibility to Atherosclerosis

Biddinger, Sudha B.; Hernandez-Ono, Antonio; Rask-Madsen, Christian; Haas, Joel T.; Alemán, José O.; Suzuki, Ryo; Scapa, Erez F.; Agarwal, Chhavi; Carey, Martin C.; Stephanopoulos, Gregory; Cohen, David E.; King, George L.; Ginsberg, Henry N.; Kahn, C. Ronald

doi:10.1016/j.cmet.2007.11.013

Cited by 469Lipid metabolism and disordersCholesterol and Lipid MetabolismDiabetes, Cardiovascular Risks, and Lipoproteins

Hepatic Insulin Resistance Is Sufficient to Produce Dyslipidemia and Susceptibility to Atherosclerosis

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Biddinger, Sudha B., Hernandez-Ono, Antonio, Rask-Madsen, Christian, Haas, Joel T., Alemán, José O., Suzuki, Ryo, Scapa, Erez F., Agarwal, Chhavi +6 more·2008·Cell Metabolism

DOI 10.1016/j.cmet.2007.11.013PMC PMC4251554

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Abstract

Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a standard chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced high-density lipoprotein (HDL) cholesterol and very low-density lipoprotein (VLDL) particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apolipoprotein B-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of Pgc-1 beta (Ppargc-1b), which promotes VLDL secretion, but decreased expression of Srebp-1c (Srebf1), Srebp-2 (Srebf2), and their targets, the lipogenic enzymes and the LDL receptor. Within 12 weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome.

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LIRKO mice are susceptible to atherosclerosis.
“They are also susceptible to atherosclerosis (15).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [15]
LIRKO mice cannot respond to insulin in the liver and display features of diabetes such as hyperglycemia, hyperinsulinemia, and dyslipidemia.
“Liver insulin receptor knockout (LIRKO) mice are unable to respond to insulin in the liver and display several features of diabetes, such as hyperglycemia, hyperinsulinemia, and dyslipidemia.”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [15]
LIRKO mice are also dyslipidemic and susceptible to atherosclerosis.
“Interestingly, these mice are also dyslipidemic and susceptible to atherosclerosis (209).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [209]

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Mechanisms of Insulin Action and Insulin Resistance
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Clinical significance of apolipoprotein measurements
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Authors: Biddinger, S. B., Hernandez-Ono, A., Rask-Madsen, C., Haas, J. T., Alemán, J. O., Suzuki, R., Scapa, E. F., Agarwal, C., Carey, M. C., Stephanopoulos, G., Cohen, D. E., King, G. L., Ginsberg, H. N., & Kahn, C. R.
Affiliations: Joslin Diabetes Center (US)
Massachusetts Institute of Technology (US)
Brigham and Women's Hospital (US)
Columbia University (US)
Corresponding author: Kahn, C. Ronald
ORCID: Biddinger, Sudha B.
Haas, Joel T.
Alemán, José O.
Suzuki, Ryo
Agarwal, Chhavi
Stephanopoulos, Gregory
Cohen, David E.
King, George L.
Ginsberg, Henry N.
Kahn, C. Ronald
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2008-02
Volume: 7
Issue: 2
Pages: 125-134
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2007.11.013
PMC: PMC4251554
OpenAlex: W2019973807
Cited by: 469
References: 80
Citations by year: 2026: 15 · 2025: 20 · 2024: 17 · 2023: 16 · 2022: 17 · 2021: 23 · 2020: 17 · 2019: 22 · 2018: 26 · 2017: 23 · 2016: 30 · 2015: 33 · 2014: 27 · 2013: 25 · 2012: 26
FWCI: 32.02
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2029 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (R01HL073030, HL73030, HL55368)
National Institute of Diabetes and Digestive and Kidney Diseases (R37DK031036, DK073687, K08DK073358, R01DK031036, DK45935, R01DK053105, DK31036, P30-DK36836, DK75850, U24DK059637, DK59637-01, DK-036588, R01DK073687, R01DK045935, R01DK056626, K12DK063696, R37DK048873, R01DK075850, DK053105, P30DK036836, R01DK048873)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: hepatic insulin resistance, dyslipidemia, atherosclerosis, metabolic syndrome, cardiovascular disease, apolipoprotein B-containing lipoproteins, VLDL secretion, HDL cholesterol, SREBP-1c, SREBP2, LDL receptor, hypercholesterolemia, atherogenic diet, lipogenic enzymes
MeSH terms: Animals, Disease Susceptibility, Hypercholesterolemia, Insulin Resistance, Lipoproteins, Liver Diseases, Receptor, Insulin, Mice, Knockout, Dyslipidemias, Atherosclerosis, Mice

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Hepatic Insulin Resistance Is Sufficient to Produce Dyslipidemia and Susceptibility to Atherosclerosis

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