Intermediate filament protein vimentin propels intrahepatic lipid accumulation in insulin-resistant mice.

Insulin resistance is known for promoting lipid accumulation in hepatocytes mainly by enhancing hepatic de novo lipogenesis (DNL), thereby playing a role in the development and progression of metabolic dysfunction-associated fatty liver disease (MAFLD). Nonetheless, the paradox persists that hepatocytes sustain enhanced DNL activity despite compromised insulin signaling. The molecular mechanisms that sustain this lipogenic drive in the presence of insulin resistance remain inadequately elucidated, highlighting a significant deficiency in our comprehension of MAFLD etiology. In this study, we observed that a high-fat diet (HFD) increases the expression and release of Vimentin from Kupffer cells (KCs), which, in turn, cross-talks with the hepatocytes' IGF1 receptor to sequester LKB1 in the nucleus and repress AMPK activation. Serum vimentin levels were elevated in patients with MAFLD and the HFD-induced MAFLD mouse model. Interestingly, both KC depletion and the Vimentin knockdown attenuated intrahepatic fat accumulation. Moreover, supplementation of recombinant Vimentin in KC-depleted HFD mice resulted in increased intrahepatic lipid accumulation, suggesting a plausible role of Vimentin in the pathophysiology of MAFLD. Mechanistically, HFD increased Vimentin expression. Upon secretion from KCs, Vimentin interacts with IGF1 receptor of the hepatocytes, leading to reduced hepatic AMPK activation and enhanced DNL. Thus, the study shows that obesity promotes hepatic DNL in the insulin-resistant state via Vimentin, a hitherto unknown organokine.