PARK7 deficiency inhibits fatty acid β‐oxidation via PTEN to delay liver regeneration after hepatectomy

Abstract

Background & aims Transient regeneration–associated steatosis (TRAS) is a process of temporary hepatic lipid accumulation and is essential for liver regeneration by providing energy generated from fatty acid β‐oxidation, but the regulatory mechanism underlying TRAS remains unknown. Parkinsonism‐associated deglycase (Park7)/Dj1 is an important regulator involved in various liver diseases. In nonalcoholic fatty liver diseased mice, induced by a high‐fat diet, Park7 deficiency improves hepatic steatosis, but its role in liver regeneration remains unknown Methods Park7 knockout (Park7−/−), hepatocyte‐specific Park7 knockout (Park7△hep) and hepatocyte‐specific Park7‐Pten double knockout mice were subjected to 2/3 partial hepatectomy (PHx) Results Increased PARK7 expression was observed in the regenerating liver of mice at 36 and 48 h after PHx. Park7−/− and Park7△hep mice showed delayed liver regeneration and enhanced TRAS after PHx. PPARa, a key regulator of β‐oxidation, and carnitine palmitoyltransferase 1a (CPT1a), a rate‐limiting enzyme of β‐oxidation, had substantially decreased expression in the regenerating liver of Park7△hep mice. Increased phosphatase and tensin homolog (PTEN) expression was observed in the liver of Park7△hep mice, which might contribute to delayed liver regeneration in these mice because genomic depletion or pharmacological inhibition of PTEN restored the delayed liver regeneration by reversing the downregulation of PPARa and CPT1a and in turn accelerating the utilization of TRAS in the regenerating liver of Park7△hep mice Conclusion Park7/Dj1 is a novel regulator of PTEN‐dependent fatty acid β‐oxidation, and increasing Park7 expression might be a promising strategy to promote liver regeneration.

Augmenter of liver regeneration knockout aggravates tubular ferroptosis and macrophage activation by regulating carnitine palmitoyltransferase‐1A‐induced lipid metabolism in diabetic nephropathy

“…After screening by MS analysis for fatty acid metabolism‐related proteins that interact with ALR, 7 candidate proteins were detected, including HADHB , CPT1A , TECR , HSD17B4 , ACSL4 , HSD17B12 , and HACD3 (Table 2, Figure 7H). Among these proteins, CPT1A, the known rate‐ limiting enzyme of FAO, 35 was reported to reduces M1 macrophage infiltration in CPT1A‐knockin mice 36 . In the idiopathic pulmonary fibrosis model, M1 macrophages disrupted fatty acid metabolism, which manifested as reduced FAO activity and decreased CPT1A expression 37 .…”

Integrative analysis of the transcriptome and metabolome reveals the importance of hepatokine FGF21 in liver aging

“…Peroxisomes, fatty acid metabolism, and liver regeneration are interconnected. 70 The decrease in peroxisomes showed that aged livers have a reduced ability to withstand oxidative stress and that lipid metabolism and fatty acid oxidation are thus compromised. Such compromised fatty acid metabolism leads to a decreased energy supply, but liver regeneration is energy-consuming, which decreases the capability for liver regeneration.…”

Integrated analysis of lncRNA/circRNA–miRNA–mRNA in the proliferative phase of liver regeneration in mice with liver fibrosis

“…Lipid metabolism has an important role in liver regeneration [42,45]. Indeed, fatty acid oxidation is the main source of energy for liver regeneration, and inhibition of fatty acid β-oxidation has been reported to delay liver regeneration after hepatectomy [46]. Cholesterol affects liver regeneration by regulating cell cycle progression [47], and steroids inhibit liver regeneration by suppressing TNF-α and IL-6 overproduction and hepatocyte DNA synthesis [48,49].…”