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Transmembrane 6 superfamily member 2 (TM6SF2) is located on chromosome 19 (19p12) and encodes for a protein of undetermined function. Genetic studies have reported the association between a nonsynonymous variant in TM6SF2 (E167K, rs58542926) with hepatic triglyceride content and its impact on the cardiovascular system. Clinical and epidemiological studies have confirmed the role of TM6SF2 in the development of nonalcoholic fatty liver disease (NAFLD). Recently, TM6SF2 was also shown to play an important role in promoting hepatic fibrosis and hepatocellular cancer in mouse models. This review aims to capture the physiological role of TM6SF2 in the regulation of lipid metabolism and its involvement in cardiometabolic diseases.