# Tspo Depletion Exacerbates Steatosis Through Fatty Acid Uptake

## TL;DR

This study shows that Tspo deficiency worsens fatty liver disease by increasing fat uptake and impairing liver cell function.

## Contribution

The study reveals a novel mechanism by which Tspo depletion exacerbates steatosis through CD36-mediated fatty acid uptake and mitochondrial dysfunction.

## Key findings

- Tspo KO rats on a GAN diet showed increased insulin resistance and higher hepatic TAG levels.
- Tspo depletion increased CD36 expression and FFA uptake, impairing mitochondrial function and autophagy.
- TSPO interacts with CPT1A to facilitate fatty acid oxidation, and its loss disrupts this process.

## Abstract

Previous studies demonstrated that Tspo loss causes simple steatosis (SS) in hepatocytes in vitro. However, its effect on SS in vivo remains unclear. In this study, we hypothesise that Tspo loss promotes early‐stage MASLD. WT and Tspo KO rats were fed a Gubra Amylin NASH (GAN) diet for 8 weeks to induce SS. Tspo KO rats fed the GAN diet (KO GAN) exhibited increased insulin resistance, higher plasma cholesterol, and elevated hepatic triacylglycerol (TAG) levels, along with higher de novo lipogenesis (DNL) and free fatty acid (FFA) uptake, evidenced by increased fatty acid synthase (FASN) and CD36 expression. The Acyl‐coenzyme A binding protein/diazepam‐binding inhibitor‐TSPO complex facilitated FA transport to the mitochondria, where carnitine palmitoyltransferase 1A (CPT1A) directed them for β‐oxidation. TSPO interacted with CPT1A in the outer mitochondrial membrane, while its depletion increased CPT1A expression, boosting FA oxidation. Primary Tspo KO rat hepatocytes and stably overexpressed CD36 (CD36_OE) in Huh7 cells displayed impaired mitochondrial function and compromised mitochondrial membrane potential. KO GAN livers had significantly elevated AcCoA, which acetylated RAPTOR, activating mTORC1 to suppress autophagy. Overall, Tspo deficiency exacerbates the advancement of SS by enhancing CD36‐mediated FFA uptake, elevating AcCoA levels, compromising mitochondrial function and impairing autophagy during the early stages of MASLD.