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Monocyte chemoattractant protein-1-induced protein-1 (MCPIP1) acts as an endonuclease that degrades selected mRNAs, viral RNAs and pre-miRNAs. MCPIP1 inhibits adipogenesis by degradation of C/EBPβ mRNA and adipogenesis-related miRNA, however its role in the regulation of hepatic lipid homeostasis is unknown. In this study, we investigated the role of MCPIP1 in the regulation of lipid metabolism in hepatocytes. C57BL/6 mice were fed a high-fat diet (HFD) for 2–20 weeks and next primary hepatocytes and adipose tissue were isolated. For in vitro experiments we used murine primary hepatocytes, control HepG2 cells and HepG2 with overexpressed or silenced MCPIP1. We found that Mcpip1 levels were lower in primary hepatocytes isolated from HFD-fed mice than in control cells starting at 4 weeks of a HFD. Level of Mcpip1 was also depleted in visceral fat isolated from obese and glucose-intolerant mice characterized by fatty liver disease. We showed that MCPIP1 overexpression in HepG2 cells treated with oleate induces the level and activity of peroxisome proliferator-activated receptor γ (PPARγ). This phenotype was reverted upon silencing of MCPIP1 in HepG2 cells and in primary hepatocytes lacking Mcpip1 protein. MCPIP1 activated the PPARγ transcription factor via the thioredoxin-interacting protein (TXNIP)/peroxisome proliferator-activated receptor γ coactivator 1- α (PGC-1α) pathway. MCPIP1 contributes to lipid metabolism in hepatocytes by regulating the TXNIP/PGC-1α/PPARγ pathway.