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Receptor Biology and Signal Transduction

ORF29-04 - HNF4 Α Isoforms Regulate Interorgan Crosstalk during Fasting, Cold Exposure and Exercise

Sunday, June 14, 2026
2:00 PM - 2:15 PM CT
Location: Room W180

Hepatocyte Nuclear Factor 4 alpha (HNF4α) is a nuclear receptor that serves as a master regulator of liver-specific gene expression and plays a central role in hepatic lipid and energy metabolism. The human HNF4A and mouse Hnf4a genes are highly conserved and regulated by two promoters: the proximal P1 and distal P2 promoters which drive expression of HNF4α isoforms with altered N-terminal domains. Although P2-HNF4α is absent in normal adult liver, its expression can be induced under conditions of metabolic stress including cancer, alcoholic fatty liver disease and high fat diet feeding. To investigate the physiological role of P2-HNF4α under conditions of metabolic extremes, we subjected HNF4α exon swap mice which express either P1 (α1HMZ)- or P2 (α7HMZ)-HNF4α isoforms to prolonged fasting, cold exposure, and/or spontaneous wheel running (SWR). Body weight, blood glucose, circulating ketone bodies, body temperature, and physical activity (SWR) were monitored. Liver and adipose tissues were collected for analysis of mitochondrial function/ketogenesis gene expression (NanoString) and mitochondrial function (Seahorse). α7HMZ mice, especially males, displayed enhanced ketogenesis during fasting and cold exposure and more wheel running compared to a1HMZ mice. α7HMZ males lost more body temperature upon prolonged exposure to a temperature of 4℃ compared to females and other genotypes. α7HMZ livers exhibited significantly increased expression of genes such as Abcd3, Cd36, Coq2, Cpt1a, Hmgcs2, Pdk4 in response to one or more of the metabolic stressors -- fasting, cold exposure and SWR. Consistently, mitochondrial function in the liver is significantly higher in α7HMZ males than α1HMZ males after a one month SWR regimen. We also observed significant tissue-specific differences in mitochondrial gene expression between liver and brown adipose tissue (Fgf21, Plin2, Nfel2), as well as stressor-specific transcriptional responses within the same tissue (Acot2, Ehhadh, Fabp1). Additional sex-specific differences were observed between the HNF4α isoforms (Dhrs7b, Ndufs2, Slc25a5). Collectively, these findings suggest that P2-HNF4α coordinately regulates an evolutionarily conserved metabolic adaptation that involves the mitochondria, thereby promoting interorgan crosstalk and hence survival during sustained metabolic stress.