Abstract
Acute fasting causes elevated oxidative stress. The current study investigated the effects of the nuclear factor erythoid 2-related factor 2 (Nrf2), the sensor of oxidative stress in cells, on energy homeostasis and liver pathophysiology during fasting. Feed was removed from mice possessing none (Nrf2-null), normal (wild-type, WT), enhanced (Keap1-knockdown, K1-KD), and maximum (hepatocyte-specific Keap1-knockout, K1-HKO) Nrf2 activity in liver for 24 h. Body weight, blood glucose, and blood lipid profiles were similar among mice with graded Nrf2 activity under either fed or fasted conditions. Fasting reduced liver size in mice expressing Nrf2, but not in Nrf2-null mice. Nrf2-null mice accumulated more non-esterified free fatty acids and triglycerides in liver after fasting than the other genotypes of mice. Fatty acids are mainly catabolized in mitochondria, and Nrf2-null mice had lower mitochondrial content in liver under control feeding conditions, which was further reduced by fasting. In contrast, mitochondrial contents in mice with enhanced Nrf2 activity were not affected by fasting. Oxidative stress, determined by staining of free radicals and quantification of malondialdehyde equivalents, was highest in Nrf2-null and lowest in K1-HKO mice after fasting. The exacerbated oxidative stress in livers of Nrf2-null mice is predicted to lead to damages to mitochondria, and therefore diminished oxidation and increased accumulation of lipids in livers of Nrf2-null mice. In summary, the Nrf2-regulated signaling pathway is critical in protecting mitochondria from oxidative stress during feed deprivation, which ensures efficient utilization of fatty acids in livers of mice.
Highlights
Starvation is a common situation for living organisms
Several research groups have investigated the effects of nuclear factor erythoid 2related factor 2 (Nrf2) activation on energy homeostasis and the development of diabetes in mice fed a high-fat diet [11,12,13,14,15,16,17,18,19,20]
The current study investigated the effects of genetic ablation or activation of Nrf2 on energy homeostasis in mice that were deprived of feed for 24 h
Summary
Starvation is a common situation for living organisms. Complex metabolic systems have evolved to help mammals adapt to food deprivation. The liver plays a central role in maintaining wholebody energy homeostasis during fasting. In the initial stage of fasting, liver glycogen is mobilized to replenish blood glucose (glycogenolysis). Triglycerides stored in adipose tissue are released into the circulation in the form of glycerol and fatty acids. The glycerol is converted into glucose by hepatic gluconeogenesis. The fatty acids are either directly oxidized to generate energy by liver and muscle, or transformed into ketone bodies by the liver. Ketone bodies can be utilized for gluconeogenesis by the liver, or used as fuel for tissues, such as brain, which cannot use fatty acids. Fat reserves are exhausted and muscle degradation occurs to send amino acids to the liver as another substrate for gluconeogenesis [1]
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