UC Riverside

Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of liver-specific gene expression, is regulated by two promoters (P1 and P2) which drive expression of two groups of HNF4α isoforms. HNF4α is a known regulator of gluconeogenesis and is mutated in maturity onset diabetes of the young one (MODY1). Moreover, HNF4α is heavily involved in regulating both lipid and glucose metabolism in the liver. Conventionally, it was thought that P1-HNF4α, but not P2-HNF4α, is expressed in the normal adult liver, while P1-HNF4α is downregulated and P2-HNF4α is upregulated in fetal liver as well as in liver cancer. This dissertation explores a previously undescribed role for P2-HNF4α in the normal adult mouse liver – one involved in the diurnal variations of lipid and carbohydrate metabolism. More specifically, P1-HNF4α appears to be a major driver of gluconeogenesis while P2-HNF4α is a driver of ketogenesis. We utilize P1-HNF4α-expressing (α1HMZ) and P2-HNF4α-expressing exon swap mice (α7HMZ) to determine the physiological function of the HNF4α isoforms in the switch between gluconeogenesis and ketogenesis, and to characterize the impact of sex on those functions. Additionally, we use AICAR treatment to explore the effect of AMP-Activated Protein Kinase (AMPK) activation in these mice, as AMPK, an energy-sensing kinase, has been shown to phosphorylate P1-HNF4α in vitro. Finally, given the fact metabolism in general can heavily affect the aging process and more specifically that ketone bodies serve as a source of fuel for the brain, and have been implicated in prevention of neurological diseases, such as dementia, we explore the effect of differential HNF4α expression in aging mice. The compelling data showing HNF4α isoforms are involved in the switch between gluconeogenesis and ketogenesis, a basic metabolic process that occurs on a daily basis, illuminate not only the molecular mechanism underlying the switch but also how that mechanism is impacted by sex. These studies have the potential to impact our understanding of numerous metabolic diseases, including diabetes, obesity, fatty liver disease and cancer.