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Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Liver-specific Expression of HIV-1 Viral Protein R Causes Hepatic Steatosis and Glucose Intolerance in Male Mice
Neeti Agarwal1, Pradip Saha1, Claudia E Ramirez Bustamante1
1Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, TX 77030, USA.
Background:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized in people with HIV (PWH), with both HIV and antiretroviral therapy contributing to liver damage and glucose intolerance. However, the role of viral proteins derived from reservoirs in this process remains unclear.
Methods:
Adeno-associated virus (AAV) constructs encoding a control protein or HIV-1 viral protein R (Vpr) driven by the thyroxine-binding globulin promoter were administered to male mice (n = 5 per group) fed regular chow or a high-fat diet (HFD). Young adult mice underwent intraperitoneal glucose tolerance testing and magnetic resonance imaging, followed by euthanasia. Liver and adipose tissues were analyzed for mRNA expression, lipid levels, and fat content and plasma samples for triglycerides and liver function.
Results:
AAV-Vpr mice on HFD developed exacerbated hepatic steatosis, glucose intolerance, and systemic inflammation compared to AAV-green fluorescent protein control mice. Gene expression indicated enhanced de novo lipogenesis, diminished lipid oxidation and insulin resistance in the liver. These effects were distinct from those observed with HFD alone, confirming a Vpr-specific contribution.
Conclusion:
Vpr upregulates the hepatic synthesis of fatty acids and downregulates their oxidation and export as triglycerides. The liver-specific activity of Vpr is sufficient, in synergy with a HFD, to cause hepatic steatosis and impaired glucose tolerance. These findings define a tissue-autonomous role for Vpr in mediating hepatic steatosis in mice, with implications for MASLD development and its complications in PWH.
Insights
HIV-1 viral protein R (Vpr) drives metabolic dysfunction-associated steatotic liver disease (MASLD) in mice. Vpr exacerbates hepatic steatosis and glucose intolerance, particularly with high-fat diets, highlighting its role in liver damage for people with HIV.
Area of Science:
- Hepatology
- Virology
- Metabolic Diseases
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing concern in people with HIV (PWH).
- Both HIV infection and antiretroviral therapy contribute to liver damage and glucose intolerance in PWH.
- The specific role of viral proteins from HIV reservoirs in MASLD pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of HIV-1 viral protein R (Vpr) in the development of MASLD.
- To determine if Vpr contributes to hepatic steatosis and glucose intolerance, independent of or in synergy with a high-fat diet (HFD).
Main Methods:
- Adeno-associated virus (AAV) constructs encoding Vpr or a control protein were administered to mice on regular chow or HFD.
- Mice underwent glucose tolerance testing and MRI, followed by tissue analysis (liver, adipose) for gene expression, lipids, and fat content.
- Plasma samples were analyzed for triglycerides and liver function markers.
Main Results:
- Mice expressing AAV-Vpr on an HFD exhibited worsened hepatic steatosis, glucose intolerance, and systemic inflammation compared to controls.
- Gene expression analysis revealed increased de novo lipogenesis and reduced lipid oxidation and insulin sensitivity in the livers of AAV-Vpr mice.
- These Vpr-specific effects were distinct from those caused by HFD alone, confirming Vpr's contribution.
Conclusions:
- HIV-1 Vpr upregulates fatty acid synthesis and impairs lipid oxidation and export in the liver.
- Vpr's liver-specific activity, combined with an HFD, is sufficient to induce hepatic steatosis and glucose intolerance.
- These findings establish a direct role for Vpr in mediating hepatic steatosis, with significant implications for MASLD in people with HIV.
