Pharmacological effects of mTORC1/C2 inhibitor in a preclinical model of NASH progression

by Selleckchem | Dec 13 2023

Knowledge of the benefits of mTOR inhibition concerning adipogenesis and inflammation has recently encouraged the investigation of a new generation of mTOR inhibitors for non-alcoholic steatohepatitis (NASH). We investigated whether treatment with a specific mTORC1/C2 inhibitor (Ku-0063794; KU) exerted any beneficial impacts on experimentally-induced NASH in vitro and in vivo. The results indicated that KU decreases palmitic acid-induced lipotoxicity in cultivated primary hepatocytes, thus emerging as a successful candidate for testing in an in vivo NASH dietary model, which adopted the intraperitoneal KU dosing route rather than oral application due to its significantly greater bioavailability in mice. The pharmacodynamics experiments commenced with the feeding of male C57BL/6 mice with a high-fat atherogenic western-type diet (WD) for differing intervals over several weeks aimed at inducing various phases of NASH. In addition to the WD, the mice were treated with KU for 3 weeks or 4 months. Acute and chronic KU treatments were observed to be safe at the given concentrations with no toxicity indications in the mice. KU was found to alleviate NASH-related hepatotoxicity, mitochondrial and oxidative stress, and decrease the liver triglyceride content and TNF-α mRNA in at least one set of in vivo experiments. The KU modulated liver expression of selected metabolic and oxidative stress-related genes depended upon the length and severity of the disease. Although KU failed to completely reverse the histological progression of NASH in the mice, we demonstrated the complexity of mTORC1/C2 signaling regulation and suggest a stratified therapeutic management approach throughout the disease course.

Comments:

The information you provided describes a study investigating the effects of a specific mTORC1/C2 inhibitor, Ku-0063794 (KU), on non-alcoholic steatohepatitis (NASH) in both in vitro and in vivo settings. Here's a summary of the key points from the study:

**Background:**
- **mTOR Inhibition:** The study focuses on mTOR inhibition as a potential treatment for NASH, considering the known benefits of mTOR inhibition concerning adipogenesis and inflammation.

**In Vitro Findings:**
- **Palmitic Acid-Induced Lipotoxicity:** KU treatment was effective in decreasing palmitic acid-induced lipotoxicity in cultivated primary hepatocytes, indicating its potential as a treatment for NASH-related liver damage in vitro.

**In Vivo Experiments:**
- **Animal Model:** Male C57BL/6 mice were fed a high-fat atherogenic western-type diet (WD) to induce various phases of NASH.
- **KU Treatment:** Mice were treated with KU for either 3 weeks (acute treatment) or 4 months (chronic treatment) using intraperitoneal dosing due to its higher bioavailability in mice.
- **Safety:** Both acute and chronic KU treatments were deemed safe with no observable toxicity in the mice at the given concentrations.
- **Positive Effects of KU:**
- **Alleviation of NASH-Related Damage:** KU treatment alleviated NASH-related hepatotoxicity and reduced mitochondrial and oxidative stress.
- **Reduction in Triglyceride Content:** KU treatment decreased the liver triglyceride content, a common feature in NASH.
- **Modulation of Gene Expression:** KU modulated the expression of specific metabolic and oxidative stress-related genes in the liver, with effects varying based on the duration and severity of the disease.
- **Decrease in Inflammatory Marker:** KU treatment led to a decrease in TNF-α mRNA, indicating a reduction in inflammation in the liver tissue.

**Conclusion:**
- **Complexity of mTORC1/C2 Signaling:** While KU did not completely reverse the histological progression of NASH, the study highlights the complexity of mTORC1/C2 signaling regulation.
- **Stratified Therapeutic Approach:** The findings suggest that a stratified therapeutic management approach might be necessary throughout the course of the disease, indicating that different stages of NASH might require tailored treatment strategies.

In summary, the study demonstrates the potential of KU, an mTORC1/C2 inhibitor, in mitigating NASH-related liver damage and inflammation in mice, providing valuable insights into the complex mechanisms involved in NASH progression and potential therapeutic strategies.