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The PNPLA3-I148M Variant Confers an Antiatherogenic Lipid Profile in Insulin-resistant Patients

Luukkonen, Panu K. ; Qadri, Sami ; Lehtimäki, Tiina E. ; Juuti, Anne ; Sammalkorpi, Henna ; Penttilä, Anne K. ; Hakkarainen, Antti ; Orho-Melander, Marju LU ; Arola, Johanna and Yki-Järvinen, Hannele (2021) In The Journal of clinical endocrinology and metabolism 106(1). p.300-315
Abstract

CONTEXT: The I148M (rs738409-G) variant in PNPLA3 increases liver fat content but may be protective against cardiovascular disease. Insulin resistance (IR) amplifies the effect of PNPLA3-I148M on liver fat. OBJECTIVE: To study whether PNPLA3-I148M confers an antihyperlipidemic effect in insulin-resistant patients. DESIGN: Cross-sectional study comparing the impact of PNPLA3-I148M on plasma lipids and lipoproteins in 2 cohorts, both divided into groups based on rs738409-G allele carrier status and median HOMA-IR. SETTING: Tertiary referral center. PATIENTS: A total of 298 obese patients who underwent a liver biopsy during bariatric surgery (bariatric cohort: age 49 ± 9 years, body mass index [BMI] 43.2 ± 6.8 kg/m2), and 345 less obese... (More)

CONTEXT: The I148M (rs738409-G) variant in PNPLA3 increases liver fat content but may be protective against cardiovascular disease. Insulin resistance (IR) amplifies the effect of PNPLA3-I148M on liver fat. OBJECTIVE: To study whether PNPLA3-I148M confers an antihyperlipidemic effect in insulin-resistant patients. DESIGN: Cross-sectional study comparing the impact of PNPLA3-I148M on plasma lipids and lipoproteins in 2 cohorts, both divided into groups based on rs738409-G allele carrier status and median HOMA-IR. SETTING: Tertiary referral center. PATIENTS: A total of 298 obese patients who underwent a liver biopsy during bariatric surgery (bariatric cohort: age 49 ± 9 years, body mass index [BMI] 43.2 ± 6.8 kg/m2), and 345 less obese volunteers in whom liver fat was measured by proton magnetic resonance spectroscopy (nonbariatric cohort: age 45 ± 14 years, BMI 29.7 ± 5.7 kg/m2). MAIN OUTCOME MEASURES: Nuclear magnetic resonance profiling of plasma lipids, lipoprotein particle subclasses and their composition. RESULTS: In both cohorts, individuals carrying the PNPLA3-I148M variant had significantly higher liver fat content than noncarriers. In insulin-resistant and homozygous carriers, PNPLA3-I148M exerted a distinct antihyperlipidemic effect with decreased very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles and their constituents, and increased high-density lipoprotein particles and their constituents, compared with noncarriers. VLDL particles were smaller and LDL particles larger in PNPLA3-I148M carriers. These changes were geometrically opposite to those due to IR. PNPLA3-I148M did not have a measurable effect in patients with lower IR, and its effect was smaller albeit still significant in the less obese than in the obese cohort. CONCLUSIONS: PNPLA3-I148M confers an antiatherogenic plasma lipid profile particularly in insulin-resistant individuals.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
dyslipidemia, insulin resistance, lipoproteins, metabolic syndrome, non-alcoholic fatty liver disease, patatin-like phospholipase domain containing 3
in
The Journal of clinical endocrinology and metabolism
volume
106
issue
1
pages
300 - 315
publisher
Oxford University Press
external identifiers
  • pmid:33064150
  • scopus:85099072602
ISSN
1945-7197
DOI
10.1210/clinem/dgaa729
language
English
LU publication?
yes
id
036003f9-d3d7-4b1e-b617-fd45b253fa4f
date added to LUP
2021-01-20 08:35:11
date last changed
2022-10-02 06:20:22
@article{036003f9-d3d7-4b1e-b617-fd45b253fa4f,
  abstract     = {{<p>CONTEXT: The I148M (rs738409-G) variant in PNPLA3 increases liver fat content but may be protective against cardiovascular disease. Insulin resistance (IR) amplifies the effect of PNPLA3-I148M on liver fat. OBJECTIVE: To study whether PNPLA3-I148M confers an antihyperlipidemic effect in insulin-resistant patients. DESIGN: Cross-sectional study comparing the impact of PNPLA3-I148M on plasma lipids and lipoproteins in 2 cohorts, both divided into groups based on rs738409-G allele carrier status and median HOMA-IR. SETTING: Tertiary referral center. PATIENTS: A total of 298 obese patients who underwent a liver biopsy during bariatric surgery (bariatric cohort: age 49 ± 9 years, body mass index [BMI] 43.2 ± 6.8 kg/m2), and 345 less obese volunteers in whom liver fat was measured by proton magnetic resonance spectroscopy (nonbariatric cohort: age 45 ± 14 years, BMI 29.7 ± 5.7 kg/m2). MAIN OUTCOME MEASURES: Nuclear magnetic resonance profiling of plasma lipids, lipoprotein particle subclasses and their composition. RESULTS: In both cohorts, individuals carrying the PNPLA3-I148M variant had significantly higher liver fat content than noncarriers. In insulin-resistant and homozygous carriers, PNPLA3-I148M exerted a distinct antihyperlipidemic effect with decreased very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles and their constituents, and increased high-density lipoprotein particles and their constituents, compared with noncarriers. VLDL particles were smaller and LDL particles larger in PNPLA3-I148M carriers. These changes were geometrically opposite to those due to IR. PNPLA3-I148M did not have a measurable effect in patients with lower IR, and its effect was smaller albeit still significant in the less obese than in the obese cohort. CONCLUSIONS: PNPLA3-I148M confers an antiatherogenic plasma lipid profile particularly in insulin-resistant individuals.</p>}},
  author       = {{Luukkonen, Panu K. and Qadri, Sami and Lehtimäki, Tiina E. and Juuti, Anne and Sammalkorpi, Henna and Penttilä, Anne K. and Hakkarainen, Antti and Orho-Melander, Marju and Arola, Johanna and Yki-Järvinen, Hannele}},
  issn         = {{1945-7197}},
  keywords     = {{dyslipidemia; insulin resistance; lipoproteins; metabolic syndrome; non-alcoholic fatty liver disease; patatin-like phospholipase domain containing 3}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{300--315}},
  publisher    = {{Oxford University Press}},
  series       = {{The Journal of clinical endocrinology and metabolism}},
  title        = {{The PNPLA3-I148M Variant Confers an Antiatherogenic Lipid Profile in Insulin-resistant Patients}},
  url          = {{http://dx.doi.org/10.1210/clinem/dgaa729}},
  doi          = {{10.1210/clinem/dgaa729}},
  volume       = {{106}},
  year         = {{2021}},
}