R-α-lipoic acid does not reverse hepatic inflammation of aging, but lowers lipid anabolism, while accentuating circadian rhythm transcript profiles

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2012-03, Vol.302 (5), p.R587-R597
• Main Authors: Finlay, Liam A, Michels, Alex J, Butler, Judy A, Smith, Eric J, Monette, Jeffrey S, Moreau, Régis F, Petersen, Shay Kate, Frei, Balz, Hagen, Tory M
• Format: Article
• Language: English
• Subjects: Aging - drug effects; Aging - metabolism; Animals; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Circadian Rhythm - drug effects; Circadian Rhythm - genetics; Circadian Rhythm Signaling Peptides and Proteins - genetics; Circadian Rhythm Signaling Peptides and Proteins - metabolism; Dietary Supplements; Energy Metabolism - drug effects; Energy Metabolism - physiology; Gene Expression - drug effects; Gene Expression - physiology; Gene Expression Profiling; Hepatitis - genetics; Hepatitis - metabolism; Hepatitis - prevention & control; Lipid Metabolism - drug effects; Lipid Metabolism - physiology; Liver - drug effects; Liver - metabolism; Male; Models, Animal; Obesity, Diabetes and Energy Homeostasis; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; Rats; Rats, Inbred F344; Thioctic Acid - administration & dosage; Thioctic Acid - pharmacology; Thioctic Acid - therapeutic use
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00393.2011

To determine the effects of age and lipoic acid supplementation on hepatic gene expression, we fed young (3 mo) and old (24 mo) male Fischer 344 rats a diet with or without 0.2% (wt/wt) R-α-lipoic acid (LA) for 2 wk. Total RNA isolated from liver tissue was analyzed by Affymetrix microarray to examine changes in transcriptional profiles. Results showed elevated proinflammatory gene expression in the aging liver and evidence for increased immune cell activation and tissue remodeling, together representing 45% of the age-related transcriptome changes. In addition, age-related increases in transcripts of genes related to fatty acid, triglyceride, and cholesterol synthesis, including acetyl-CoA carboxylase-β (Acacb) and fatty acid synthase (Fasn), were observed. Supplementation of old animals with LA did not reverse the necroinflammatory phenotype but, intriguingly, altered the expression of genes governing circadian rhythm. Most notably, Arntl, Npas2, and Per changed in a coordinated manner with respect to rhythmic transcription. LA further caused a decrease in transcripts of several bile acid and lipid synthesis genes, including Acacb and Fasn, which are regulated by first-order clock transcription factors. Similar effects of LA supplementation on bile acid and lipid synthesis genes were observed in young animals. Transcript changes of lipid metabolism genes were corroborated by a decrease in FASN and ACC protein levels. We conclude that advanced age is associated with a necroinflammatory phenotype and increased lipid synthesis, while chronic LA supplementation influences hepatic genes associated with lipid and energy metabolism and circadian rhythm, regardless of age.