Journal article
Alcohol and Liver Clock Disruption Increase Small Droplet Macrosteatosis, Alter Lipid Metabolism and Clock Gene mRNA Rhythms, and Remodel the Triglyceride Lipidome in Mouse Liver
Frontiers in physiology, Vol.11, pp.1048-1048
09/07/2020
DOI: 10.3389/fphys.2020.01048
PMCID: PMC7504911
PMID: 33013449
Abstract
Heavy alcohol drinking dysregulates lipid metabolism, promoting hepatic steatosis – the first stage of alcohol-related liver disease (ALD). The molecular circadian clock plays a major role in synchronizing daily rhythms in behavior and metabolism and clock disruption can cause pathology, including liver disease. Previous studies indicate that alcohol consumption alters liver clock function, but the impact alcohol or clock disruption, or both have on the temporal control of hepatic lipid metabolism and injury remains unclear. Here, we undertook studies to determine whether genetic disruption of the liver clock exacerbates alterations in lipid metabolism and worsens steatosis in alcohol-fed mice. To address this question, male liver-specific
Bmal1
knockout (LKO) and flox/flox (Fl/Fl) control mice were fed a control or alcohol-containing diet for 5 weeks. Alcohol significantly dampened diurnal rhythms of mRNA levels in clock genes
Bmal1
and
Dbp
, phase advanced
Nr1d1
/REV-ERBα, and induced arrhythmicity in
Clock
,
Noct
, and
Nfil3
/E4BP4, with further disruption in livers of LKO mice. Alcohol-fed LKO mice exhibited higher plasma triglyceride (TG) and different time-of-day patterns of hepatic TG and macrosteatosis, with elevated levels of small droplet macrosteatosis compared to alcohol-fed Fl/Fl mice. Diurnal rhythms in mRNA levels of lipid metabolism transcription factors (
Srebf1
,
Nr1h2
, and
Ppara
) were significantly altered by alcohol and clock disruption. Alcohol and/or clock disruption significantly altered diurnal rhythms in mRNA levels of fatty acid (FA) synthesis and oxidation (
Acaca/b
,
Mlycd
,
Cpt1a
,
Fasn
,
Elovl5/6
, and
Fads1/2
), TG turnover (
Gpat1
,
Agpat1/2
,
Lpin1/2
,
Dgat2
, and
Pnpla2/3
), and lipid droplet (
Plin2/5
,
Lipe
,
Mgll
, and
Abdh5
) genes, along with protein abundances of p-ACC, MCD, and FASN. Lipidomics analyses showed that alcohol, clock disruption, or both significantly altered FA saturation and remodeled the FA composition of the hepatic TG pool, with higher percentages of several long and very long chain FA in livers of alcohol-fed LKO mice. In conclusion, these results show that the liver clock is important for maintaining temporal control of hepatic lipid metabolism and that disrupting the liver clock exacerbates alcohol-related hepatic steatosis.
Details
- Title: Subtitle
- Alcohol and Liver Clock Disruption Increase Small Droplet Macrosteatosis, Alter Lipid Metabolism and Clock Gene mRNA Rhythms, and Remodel the Triglyceride Lipidome in Mouse Liver
- Creators
- Jennifer A. Valcin - University of Alabama at BirminghamUduak S. Udoh - University of Alabama at BirminghamTelisha M. Swain - University of Alabama at BirminghamKelly K. Andringa - University of Alabama at BirminghamChirag R. Patel - University of Alabama at BirminghamSameer Al Diffalha - University of Alabama at BirminghamPaul R. S. Baker - Avanti Polar Lipids (United States)Karen L. Gamble - University of Alabama at BirminghamShannon M. Bailey - University of Alabama at Birmingham
- Resource Type
- Journal article
- Publication Details
- Frontiers in physiology, Vol.11, pp.1048-1048
- DOI
- 10.3389/fphys.2020.01048
- PMID
- 33013449
- PMCID
- PMC7504911
- NLM abbreviation
- Front Physiol
- ISSN
- 1664-042X
- eISSN
- 1664-042X
- Publisher
- Frontiers Media S.A
- Grant note
- AA020199; AA024543; AA026906 / NIH
- Language
- English
- Date published
- 09/07/2020
- Academic Unit
- Orthopedics and Rehabilitation
- Record Identifier
- 9984548855902771
Metrics
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