Liver CPT1A gene therapy reduces diet‐induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD

Abstract

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high‐fat diet (HFD)‐induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno‐associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD‐induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9‐hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD‐induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans.

Mitochondria, oxidative stress and nonalcoholic fatty liver disease: A complex relationship

“…Mitochondrial dysfunction can be also related to de‐regulation of lipid homeostasis, for example caused by carnitine palmitoyltransferase 1 (CPT‐1) inhibition in the presence of higher malonyl‐CoA levels generated at the DNL pathway 115 . Such de‐regulation is associated with the accumulation of lipid‐derived toxic metabolites such as ceramides, diacylglycerols and dicarboxylic acids.…”

Blueberry Counteracts Prediabetes in a Hypercaloric Diet-Induced Rat Model and Rescues Hepatic Mitochondrial Bioenergetics

“…Triglycerides contents in the liver samples were quantified by using a Triglycerides Colorimetric Assay kit (1155010, Cromatest ® , Linear Chemicals, Barcelona, Spain), as described previously [56].…”

Tri-Herbal Medicine Divya Sarva-Kalp-Kwath (Livogrit) Regulates Fatty Acid-Induced Steatosis in Human HepG2 Cells through Inhibition of Intracellular Triglycerides and Extracellular Glycerol Levels

“…The process of triglyceride formation is regulated by several transcriptional factors such as sterol regulatory element-binding protein 1 (SREBP1c), and CCAAT/enhancer-binding protein-α (C/EBPα), which are expressed in the hepatocytes and modulate the expression of downstream genes like fatty acid synthase (FAS), responsible for fatty acid synthesis [15]. Effective diversion of the intracellular FFA towards the mitochondrial beta-oxidation process is the task of carnitine palmitoyltransferase 1A (CPT1A) [16]. For retaining normoglycemic conditions, the liver tends to metabolize excess glucose to FFA through the process of de novo lipogenesis involving activation of transcriptional factors and lipogenic genes [17].…”