PPAR\u03b1\u2212ACOT12 axis is responsible for maintaining cartilage homeostasis through modulating de novo lipogenesis

In-Jeoung Baek,Sujeong Park,Churl-Hong Chun,Eun-Jung Jin,Ji Hyun Ryu

doi:10.1038/s41467-021-27738-y

In-Jeoung Baek, Sujeong Park + Show 3 more

Open Access

https://doi.org/10.1038/s41467-021-27738-y

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Abstract

Here, in Ppara−/− mice, we found that an increased DNL stimulated the cartilage degradation and identified ACOT12 as a key regulatory factor. Suppressed level of ACOT12 was observed in cartilages of OA patient and OA-induced animal. To determine the role and association of ACOT12 in the OA pathogenesis, we generated Acot12 knockout (KO) (Acot12−/−) mice using RNA-guided endonuclease. Acot12−/− mice displayed the severe cartilage degradation with the stimulation of matrix MMPs and chondrocyte apoptosis through the accumulation of acetyl CoA. Delivery of acetyl CoA-conjugated chitosan complex into cartilage stimulated DNL and cartilage degradation. Moreover, restoration of ACOT12 into human OA chondrocytes and OA-induced mouse cartilage effectively rescued the pathophysiological features of OA by regulating DNL. Taken together, our study suggested ACOT12 as a novel regulatory factor in maintaining cartilage homeostasis and targeting ACOT12 could contribute to developing a new therapeutic strategy for OA.

Highlights

In Ppara−/− mice, we found that an increased de novo lipogenesis (DNL) stimulated the cartilage degradation and identified ACOT12 as a key regulatory factor
We have demonstrated that ACOT12 deficiency is involved in the lipid deposition (LD) accumulation of the stimulation of de novo lipogenesis (DNL) through the accumulation of acetyl-CoA, leading to the stimulation of cartilagedegrading enzymes and apoptosis of chondrocyte
Several metabolic pathways including glycolysis and fatty acid oxidation are associated with OA pathogenesis[7]

Summary

Introduction

In Ppara−/− mice, we found that an increased DNL stimulated the cartilage degradation and identified ACOT12 as a key regulatory factor. Acot12−/− mice displayed the severe cartilage degradation with the stimulation of matrix MMPs and chondrocyte apoptosis through the accumulation of acetyl CoA. Delivery of acetyl CoA-conjugated chitosan complex into cartilage stimulated DNL and cartilage degradation. Chondrocytes embedded within the extracellular matrix maintain cartilage homeostasis by stimulating anabolic and catabolic pathways to regulate production, turnover, and degradation of cartilage matrix proteins, such as type II collagen and proteoglycan[1]. Increased levels of total free fatty acid (FFA) have been reported in OA patients[13–15] and prior to the appearance of histopathological OA features, accumulation of substantial LD in articular cartilage has been reported[9,16,17]. DNL is a highly regulated pathway and begins with acetyl-CoA as a principal building block for de novo synthesis of fatty acids[26,27]

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