Enhancing lysosomal lipid metabolism prevents the loss of Kupffer cells in non-alcoholic steatohepatitis and attenuates liver pathology

During the development of non-alcoholic steatohepatitis (NASH), liver resident Kupffer cells (KCs) are progressively lost and replaced by monocyte-derived macrophages (MdMs). The impact of KC loss on NASH pathology is not currently known. Given the important role of KCs in maintaining tissue homeostasis and clearing blood-borne antigens, we hypothesized that KC depletion contributes to NASH pathogenesis. Thus, we aimed to elucidate the mechanism(s) of KC loss and to devise a strategy to enhance KC survival during NASH. We had previously shown that lipids can cause lysosomal cell death in macrophages. Using a mouse model of NASH, we discovered that KCs also develop phagolysosomal pathology. Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and lipid metabolism that has been shown to rescue lysosomal dysfunction in other metabolic diseases. To test whether TFEB activation could protect against KC death in NASH, we generated a mouse model in which a KC-specific Cre induces expression of a TFEB overexpression construct (KCTFEB). Despite having similar body and liver weight as WT mice fed a NASH-inducing diet, KCTFEB mice had a striking preservation of KC number. Moreover, KCTFEB mice had reduced recruitment of pro-inflammatory MdMs and this was associated with lower liver triglyceride and injury. RNA sequencing of KCs from transgenic and WT mice revealed that TFEB induced the expression of several lysosomal and lipid metabolic genes. Together these findings provide important proof-of-concept evidence that KC loss contributes to disease pathology in NASH and suggest that targeting macrophage lysosomal/lipid metabolic function could be a useful strategy to enhance resident macrophage survival. Supported by grants from ADA-118IBS280, DDRCC-P30DK052574, NIH T32-AI007163, and NSF GRFP-DGE-1745038