PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments

Abstract

Common Abbreviations:Peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α); nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB); tumor necrosis factor alpha (TNFα); non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH) Transcript Profiling: GEO accession number GSE132458ABSTRACT Background and Aims: Liver is exposed to changing metabolic and inflammatory environments.It must sense and adapt to metabolic need while balancing resources required to protect itself from insult. PGC-1α is a transcriptional coactivator that both coordinates metabolic adaptation to diverse stimuli and protects against inflammation in several tissues. However, it is not known how PGC-1α integrates extracellular signals to balance metabolic and anti-inflammatory outcomes. PGC-1α exists as multiple, alternatively spliced variants expressed from different promoters. Methods: Tissue samples from transgenic mice and humans with fatty liver disease were analyzed for expression of PGC-1α isoforms and apoptosis caused by inflammatory damage.Primary mouse hepatocytes were used to identify effectors of PGC-1α activity downstream of TNFα. Results: We show in human liver that non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) preferentially activated the alternative PPARGC1A promoter. Gene expression analysis in primary mouse hepatocytes identified shared and isoform-specific roles for PGC-1α variants in response to TNFα. PGC-1α1 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNFα signaling revealed that PGC-1α4 influenced several pathways related to innate immunity and cell death. Gain-and loss-of-function models showed that PGC-1α4 specifically enhanced expression of anti-apoptotic gene programs and attenuated hepatocyte apoptosis in response to TNFα or LPS. This was in contrast to PGC-1α1, which reduced expression of a wide inflammatory gene network, but did not prevent liver cell death. Conclusions:We conclude that PGC-1α variants have distinct, yet complimentary roles in hepatic responses to inflammation and identify PGC-1α4 as an important mitigator of apoptosis.

Full-length transcriptomic analysis in murine and human heart reveals diversity of PGC-1α promoters and isoforms regulated distinctly in myocardial ischemia and obesity

“…It functions as a transcriptional coactivator, and its transcripts are assembled by alternative splicing events and are regulated by different promoters [1][2][3]. Its biological roles range mitochondrial biogenesis and mitochondrial dynamics [4] through induction of hypertrophy and atrophy in muscle cells as well as controlling inflammation in apoptosis environments [5]. PGC-1α is studied in detail in liver, skeletal muscle, neuronal cells (neurodegenerative disorders) [6,7] and cancer [8].…”

5-Aminolevulinic acid combined with sodium ferrous citrate (5-ALA/SFC) ameliorated liver injury in a murine acute graft-versus-host disease model by reducing inflammation responses through PGC1-α activation

“…PGC-1α plays a beneficial role in the regulation of hepatic steatosis and insulin resistance by enhancing the IL-10-mediated anti-inflammatory response (35,36). In addition, inflammation can be regulated through changes in cellular reactive oxygen species induced by PGC-1α (37).…”

HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models

“…Accordingly we measured a defective mitochondrial bioenergetics (Figure 2B-D) and decreased autophagic flux (Figure 4L-N) in the different CS cell models. The mitochondrial proteostasis regulator CLPX which was down-regulated in the CS cells had previously been identified as a transcriptomic target of AMPK and PGC1α (30,31), two large-scale transcriptional regulators strongly downregulated in CS cells.…”