Raman spectroscopic characterization of liver steatosis and fibrosis in a 2D and 3D in vitro thyroxine-treated hypothyroid cellular model

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Primary hypothyroidism has been associated with metabolic dysfunction-associated steatotic liver disease and, potentially, increased liver fibrosis risk. Although T4-analog drug is one of the standard treatments, its molecular effects on the liver are not fully understood. To elucidate drug-induced hepatic metabolic changes, chronic human 2D and 3D hypothyroid models were developed. The effects of T4 were assessed by Raman spectroscopy and complementary biological techniques to observe lipid and fibrotic changes. In vitro chronic hypothyroidism caused lipid droplet (LDs) accumulation in liver cells which was unaffected by T4 therapy. Notably, TSH and T4 influenced TG fatty acid saturation in different ways: T4-exposed cells accumulated monounsaturated fatty acids at the expense of saturated fatty acids. In the case of liver fibrosis, TSH treatment activated hepatic stellate cells as evidenced by increased collagen secretion and decreased LD content, regardless of T4 co-treatment. Data confirmed that TSH induced pro-inflammatory changes leading to higher inflammasome levels in a 3D liver model. These findings indicate the detrimental effects of elevated TSH levels, and it is worth noting that T4 administration does not reverse the excess of hepatic lipid overload but has the ability to alter its lipid composition. Furthermore, T4 administration did not reverse TSH-induced hepatic fibrogenesis in the hypothyroid cell models. Because micro-Raman spectroscopy is currently restricted to 2D/3D in-vitro systems, further validation in intact tissue and in vivo is warranted. In conclusion, our results highlight the importance of further research into the molecular pathways associated with chronic liver injury in patients with chronic hypothyroidism. • Primary hypothyroidism is linked to MASLD and a potential increase in liver fibrosis risk • Effects of T4-analog treatment on hypothyroid models analyzed by Raman spectroscopy • T4 did not reverse TSH-induced lipid droplet accumulation but modified their fatty acids • T4 did not reverse the activation of hepatic stellate cells by TSH • TSH caused pro-inflammatory changes, raising inflammasome and MMP-9 levels.

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