The Role of Peroxisome Proliferator­activated Receptor (PPAR) Coactivator PGC1

The liver is a key organ for whole body energy homeostasis. In both physiological and pathological conditions, the liver contributes to the adaptive responses that provide the energy necessary for sustenance of different organ functions. Alterations of hepatic physiological functions are critical in the development of nonalcoholic fatty liver disease (NAFLD), a disease spectrum ranging from nonalcoholic fatty liver without inflammation to nonalcoholic steatohepatitis (NASH). In turn, NASH can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The peroxisome proliferator­ activated receptor (PPAR)­γ coactivator 1 (PGC1) family of transcriptional coactivators act as molecular switches in many metabolic pathways. Activated in several organs upon conditions of increased energy demands, in liver the functions of PGC1s are mainly promoted during fasting. PGC1s are powerful regulators of various metabolic pathways and have substantial involvement in several diseases characterized by energetic misbalance, including cancer. We have now focused on mechanistic roles of PGC1s in the development of NAFLD, NASH and HCC.

Fig 1. Physiological roles of PGC1α and PGC1β in the liver. (Source: Nat Rev Gastroenterol Hepatol. March 2019.)

PGC1s control liver metabolism

Upon transition from the fed to the fasted state, the liver undergoes marked metabolic modifications to facilitate organism adaptation to a period of food shortage. These modifications include activation of mitochondrial metabolism, gluco­neogenesis, fatty acid β­ oxidation, ketogenesis, haeme biosynthesis and bile acid homeostasis, which are mostly controlled by PGC1s. PGC1 target genes are finely regulated in the liver under different energetic states to respond to the metabolic needs of hepatic cells. During fasting, as well as in conditions that mimic starvation and low energy disposal, PGC1 functions are regulated at both transcriptional and post­ transcriptional levels. Interestingly, PGC1α, but not PGC1β, can also be stimulated by glucocorticoids. Enhanced PGC1 activity induces the expression of pathways aimed to improve glucose and energy disposal in the liver to counteract the metabolic stress induced by food shortage. Both PGC1α and PGC1β coactivate several transcription factors and nuclear receptors to promote mitochondrial biogenesis, OXPHOS and fatty acid β­ oxidation, and compensatory actions in the regulation of these pathways have been observed when one of the two coactivators was experimentally downregulated.PGC1α alone coregulates HNF4α, FOXO1 and GR expression of gluconeogenic genes. Conversely, only PGC1β is induced by saturated fatty acid consumption, leading to increased de novo lipogenesis via coactivation of LXRα and SREBP1C. These opposite activities exerted by PGC1α and PGC1β probably prevent futile substrate cycles. At the same time, the upregulation of gluconeogenesis via PGC1α during fasting and new lipid synthesis via PGC1β in fed conditions enables fine tuning of glucose disposal by hepatic cells.

PGC1s in fatty acid β- oxidation.

Both PGC1α and PGC1β can promote the PPARα­ mediated expression of genes involved in hepatic fatty acid oxidation, notably medium­ chain acyl­ CoA dehydrogenase (MCAD) and carnitine palmitoyl transferase 1A (CPT1A).

PGC1s in de novo lipogenesis.

In mice, liver­ specific PGC1β overexpression protects the liver from lipid overload and from progression to fibrosis by increasing hepatic VLDL secretion, PGC1β also interacts with forkhead box protein A2 (FOXA2) to regulate fatty acid β­ oxidation and VLDL synthesis and secretion from the liver, thereby controlling lipid content. PGC1β activity could be influenced by nutritional status and/or be the result of the hormonal milieu under different physiological conditions.

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