Biology subjects

Besse-Patin, A.

Publications and source records attributed to Besse-Patin, A..

3 recordsLinked to original sources

bioRxiv2025

Glucagon-induced PGC-1α4/PPARγ promotes hepatic lipid storage and macrosteatosis in fasting and MASLD

The liver plays a central role in regulating the transition between fasting and feeding states, coordinating glycogen breakdown, gluconeogenesis, fatty acid catabolism, and lipid storage. Disruptions in this balance contribute to metabolic disorders, including Metabolic dysfunction Associated Steatotic Liver Disease (MASLD). Here, we identify a novel biological pathway downstream of glucagon that promotes the hepatic lipid accumulation associated with fasting. Using gain- and loss-of-function in vivo and in vitro models, we found that glucagon induces sustained expression of PGC-14, promoting lipid uptake and storage in hepatocytes by increasing PPAR{gamma} activity. Increased PPAR{gamma}/PGC-14 promotes hepatic Fsp27/Cidec expression, leading to lipid droplet expansion and triglyceride trapping in liver. Activity of the PPARGC1A alternative promoter and PGC-14 expression were higher in livers of patients with MASLD, and PGC-14 expression correlated with macrosteatosis. Consistently, persistent expression of hepatic PGC-14 in mice fed a western diet promoted macrosteatosis, exacerbated oxidative stress and altered hepatic lipid composition to resemble worsening Metabolic dysfunction Associated Steatohepatitis (MASH) in humans. Our findings demonstrate that glucagon-induced hepatic PGC-14/PPAR{gamma} activity facilitates efficient uptake and storage of lipids during fasting, but over-activation of this coordinated metabolic pathway leads to lipid accumulation and worsening of steatosis in MASLD.

physiology↗

bioRxiv2022

SUMOylation of ABCD3 restricts bile acid synthesis and regulates metabolic homeostasis

Mitochondrial anchored protein ligase (MAPL) has been shown to function as both a SUMO and ubiquitin ligase with multiple roles in mitochondrial quality control, cell death pathways and inflammation. To examine the global function of MAPL we generated a knock-out mouse model and sought functional insight through unbiased BioID, transcriptomics and metabolic analysis. MAPL KO mice are lean and highly insulin sensitive, ultimately developing fully penetrant, spontaneous hepatocellular carcinoma after 18 months. BioID revealed the peroxisomal bile acid transporter ABCD3 as a primary MAPL interacting partner, which we show is SUMOylated in a MAPL-dependent manner. MAPL KO animals showed increased bile acid secretion in vivo and in isolated primary hepatocytes, along with robust compensatory changes in the expression of enzymes synthesizing and detoxifying bile acid. In addition, MAPL KO livers showed signs of ER stress and secreted high levels of Fgf21, the starvation hormone known to drive the reduction of white fat stores and promote insulin sensitivity. Lastly, during aging all MAPL KO mice developed hepatocellular carcinomas. These data reveal a major function for MAPL in the regulation of bile acid synthesis leading to profound changes in whole body metabolism and the ultimate generation of liver cancer when MAPL is lost.

cell biology↗

bioRxiv2019

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

Liver is regularly 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-1 is a transcriptional coactivator that both coordinates metabolic adaptation to diverse stimuli and protects against inflammation. However, it is not known how PGC-1 integrates extracellular signals to balance metabolic and anti-inflammatory outcomes. PGC-1 exists as multiple, alternatively spliced variants expressed from different promoters. Primary mouse hepatocytes were used to evaluate the role(s) of different PGC-1 proteins in regulating hepatic metabolism and inflammatory signaling downstream of TNF. PGC-11 and PGC-14 were expressed in hepatocytes and expression analysis uncovered shared and isoform-specific roles for these variants linked to metabolism and inflammation. PGC-11 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNF signaling revealed that PGC-14 influenced several pathways related to innate immunity and cell death. Gain- and loss-of-function models illustrated that PGC-14 uniquely enhanced expression of anti-apoptotic gene programs and attenuated hepatocyte apoptosis in response to TNF or LPS. This was in contrast to PGC-11, which reduced the expression of a wide inflammatory gene network, but did not prevent liver cell death in response to the cytokine. We conclude that PGC-1 variants have distinct, yet complimentary roles in hepatic responses to metabolism and inflammation and identify PGC-14 as an important mitigator of apoptosis.

molecular biology↗