The mitochondrial dicarboxylate carrier prevents hepatic lipotoxicity by inhibiting white adipocyte lipolysis

Abstract

Background & aims: We have previously reported that the mitochondrial dicarboxylate carrier (mDIC [SLC25A10]) is predominantly expressed in the white adipose tissue (WAT) and subject to regulation by metabolic cues. However, the specific physiological functions of mDIC and the reasons for its abundant presence in adipocytes are poorly understood.

Methods: To systemically investigate the impact of mDIC function in adipocytes in vivo, we generated loss- and gain-of-function mouse models, selectively eliminating or overexpressing mDIC in mature adipocytes, respectively.

Results: In in vitro differentiated white adipocytes, mDIC is responsible for succinate transport from the mitochondrial matrix to the cytosol, from where succinate can act on the succinate receptor SUCNR1 and inhibit lipolysis by dampening the cAMP- phosphorylated hormone-sensitive lipase (pHSL) pathway. We eliminated mDIC expression in adipocytes in a doxycycline (dox)-inducible manner (mDIC^iKO) and demonstrated that such a deletion results in enhanced adipocyte lipolysis and promotes high-fat diet (HFD)-induced adipocyte dysfunction, liver lipotoxicity, and systemic insulin resistance. Conversely, in a mouse model with dox-inducible, adipocyte-specific overexpression of mDIC (mDIC^iOE), we observed suppression of adipocyte lipolysis both in vivo and ex vivo. mDIC^iOE mice are potently protected from liver lipotoxicity upon HFD feeding. Furthermore, they show resistance to HFD-induced weight gain and adipose tissue expansion with concomitant improvements in glucose tolerance and insulin sensitivity. Beyond our data in rodents, we found that human WAT SLC25A10 mRNA levels are positively correlated with insulin sensitivity and negatively correlated with intrahepatic triglyceride levels, suggesting a critical role of mDIC in regulating overall metabolic homeostasis in humans as well.

Conclusions: In summary, we highlight that mDIC plays an essential role in governing adipocyte lipolysis and preventing liver lipotoxicity in response to a HFD.

Lay summary: Dysfunctional fat tissue plays an important role in the development of fatty liver disease and liver injury. Our present study identifies a mitochondrial transporter, mDIC, which tightly controls the release of free fatty acids from adipocytes to the liver through the export of succinate from mitochondria. We believe this mDIC-succinate axis could be targeted for the treatment of fatty liver disease.

Keywords: NAFLD; NASH; adipocytes; dicarboxylate carrier; insulin resistance; lipolysis; lipotoxicity; mitochondria; succinate.