Extrahepatic PPARα modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice

Abstract

PPARα (PPARA), expressed in most oxidative tissues, is a major regulator of lipid homeostasis; hepatic PPARA plays a critical role during the adaptive fasting response by promoting FA oxidation (FAO). To clarify whether extrahepatic PPARA activity can protect against lipid overload when hepatic PPARA is impaired, lipid accumulation was compared in WT ( ), total body-null ( ), and hepatocyte-specific-null ( ) mice that were fasted for 24 h. Histologic staining indicated reduced lipid accumulation in versus mice, and biochemical analyses revealed diminished medium- and long-chain FA accumulation in mouse livers. Hepatic PPARA target genes were suppressed in both mouse models. Serum FFAs increased in all genotypes after fasting but were highest in mice. In mice, FAO genes were increased in brown adipose tissue, heart, and muscle, and total lipase activity was elevated in the muscle and heart, suggesting increased lipid utilization. Thus, extrahepatic PPARA activity reduces systemic lipid load when hepatic lipid metabolism is impaired by elevating FAO and lipase activity in other tissues and, as a result, protects against fasting-induced hepatosteatosis. This has important clinical implications in disease states with impaired hepatic PPARA function, such as nonalcoholic steatohepatitis and nonalcoholic fatty liver disease.

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

“…PPARA plays an important role in the fasted mouse liver model (Brocker et al, 2018). Hepatic expression of PPARA target genes Acadm and Cyp4a14 was significantly increased by fasting, as was the expression of Txnip mRNA, as was seen in livers of Gm15441 LSL mice as well as Gm15441 +/+ mice compared with fed mice.…”

“…PPARA, a key regulator of global lipid homeostasis, modulates fasting-induced lipid accumulation and hepatosteatosis in mice (Brocker et al, 2018). Lipid droplets appeared in livers of fasted Gm15441 +/+ mice but were more widely distributed in livers of fasting Gm15441 LSL mice compared to fasting Gm15441 +/+ mice.…”

“…Fasting also increased TXNIP, CASP1, and IL1B protein levels in Gm15441 LSL mice, in contrast to either a modest increase (TXNIP) or no increase (CASP1, IL1B) in Gm15441 +/+ mice (Figure S2B, Figure S2C). Fasting markedly promotes lipid accumulation in mouse liver (Brocker et al, 2018). Lipid droplet accumulation was also observed and more widespread in fasting Gm15441 LSL mice than fasting Gm15441 +/+ mice (Figure S2D).…”

“…During fasting, hepatic PPARA facilitates the metabolic remodeling that promotes use of lipids as an alternate energy source (Brocker et al, 2018). Fasting is also associated with many anti-inflammatory effects (Corrales et al, 2019).…”

“…Peroxisome proliferator-activated receptor alpha (PPARA) is a ligand-activated nuclear receptor and transcription factor that is a key regulator of the fasting response. PPARA facilitates metabolic remodeling that promotes lipid oxidation, and its dysregulation contributes to metabolic disorders and liver disease (Brocker et al, 2018). Further, synthetic PPARA agonists act as potent antiinflammatory agents Zheng et al, 2017).…”