Curcumin and saroglitazar attenuate diet-induced nonalcoholic steatohepatitis by activating the Nrf2 pathway and suppressing ERK1/2 signaling.

Objectives: Non-alcoholic fatty liver disease (NAFLD) is a chronic steatohepatitis disorder. If left untreated, it can progress to hepatocellular carcinoma. Several studies have shown that saroglitazar, a PPARα/γ dual agonist, and curcumin (the principal constituent of turmeric) may be effective in the treatment of NAFLD. This research aimed to study the pharmacological mechanism of these compounds in rats with NAFLD. Materials and Methods: NAFLD was induced in male Wistar rats (aged 6-8 weeks) by feeding them a high-fat diet (HFD) for 6 weeks. Subsequently, the rats were divided into four groups, with Group 1 continuing on HFD, while groups 2, 3, and 4 received HFD supplemented with saroglitazar, curcumin, and both saroglitazar and curcumin, respectively. We evaluated the expression of Nrf2, ERK1/2, NOX1,2,4, antioxidant enzymes, PPARα, γ, and genes regulating lipid metabolism in the liver. Histopathology of liver tissue was also examined. Furthermore, we analyzed serum levels of lipid profiles and hepatic enzymes. Results: Rats with NAFLD that received treatment involving saroglitazar and curcumin showed a significant decrease in the expression of ERK1/2, SREBP1, PPARγ, pro-inflammatory cytokines, NOXs, and ROS levels. Additionally, the levels of Nrf2, PPARα, and antioxidant enzymes showed a significant increase. The serum levels of lipid profiles and hepatic enzymes also decreased significantly after drug treatment. Conclusion: Our results confirm that both saroglitazar and curcumin ameliorate NAFLD by regulating the Nrf2 and ERK1/2 signaling pathways. These findings suggest that curcumin could serve as a suitable substitute for saroglitazar, although they appear to have a synergistic effect.

Amyloid Beta Alters the Expression of microRNAs Regulating HMGCR and ABCA1 Genes in Astrocytes of C57BL/6J Mice.

Dysregulation of brain cholesterol homeostasis causes the accumulation of extracellular protein deposits called amyloid plaques in the hippocampus which eventually leads to neuronal death, memory and learning deficits. The aim of the present study was to investigate the effect of beta amyloid on miRNAs regulating HMGCR and ABCA1 as cholesterol synthesis and homeostasis genes. Primary astrocytes were isolated from C57BL/6J mice, and were treated with 0.5 µM amyloid beta (Aß). Expression levels of genes and miRNAs were measured by real-time PCR. In comparison to control, Aß treatment resulted in a significant decrease in miR-96-5p expression as a positive and negative regulator of HMGCR and ABCA1, respectively. There was no significant increase in miR-27a-3p expression as a negative regulator of HMGCR. miR- 106b- 5p and miR-143-3p expressions were also dramatically decreased as ABCA1 negative regulators. Amyloid beta can alter the expression of major genes in the cholesterol homeostasis pathway via their regulatory miRNAs.