Kupffer cells (KCs) are vital innate immune system cells in the liver that participate in various metabolic states. Although several studies have directly evaluated the role of KCs in different metabolic situations in the liver, the definite characteristics of KCs remain unknown. KC depletion techniques are used to determine the functions of KCs under metabolic challenges; however, there is debate about their precise role even after successful ablation. While some KC ablation studies showed improvement in insulin resistance, fatty liver and metabolic parameters, other reports, under the similar conditions, have not. Some studies have rationalized the KCs dual actions in liver metabolic states by arguing their M1 and M2 biases. Activated M1 KCs secrete pro-inflammatory cytokines, growth factors and other mediators to create inflammatory stress which initiates inflammatory signalling in hepatocytes to disrupt the metabolic scenario. In contrast, M2 KCs generate anti-inflammatory cytokines and mediators which improve glucose and lipid metabolic states within the liver. Unfortunately, the M1/M2 bias does not provide reliable explanation as KCs depletion shows strikingly different results. Despite many investigational studies on this topic, a comprehensive review of these studies is lacking. This review attempts to address the issues related with the dichotomy of KCs effects in lipid metabolism. This review not only warns the future studies to carefully analyze the results that are drawn from KCs effects on lipid metabolism but also suggest to evaluate animal models and KCs depletion techniques as an equally important cofactor.
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