Non-alcoholic fatty liver disease (NAFLD) is an umbrella term for a range of conditions caused by a build-up of fat in the liver. It is usually seen in people who are overweight or obese. Increasingly common around the world, this disease is the most common chronic liver disease in the United States, affecting about a quarter of the population. Recently, the designation of NAFLD as 'metabolic dysfunction-associated fatty liver disease' (MAFLD) has been a subject of current debate. In this context, 'insulin resistance' is the underlying common and basic pathophysiological mechanism of metabolic dysfunction due to its association with obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome, dyslipidemia and NAFLD. All these pathological conditions are among the metabolic risk factors for cardiovascular diseases, too. Also, due to the bidirectional causality between NAFLD and cardiovascular diseases, a liver-heart axis is suggested. Therefore, various factors such as insulin resistance as well as systemic inflammation, cytokines, oxidative stress, adipokines, hepatokines, genes and intestinal microbiota have been identified as possible pathogenic factors that play a role in the explanation of the complex NAFLD and cardiovascular risk relationship. Recent data and cumulative evidence show that electronegative low-density lipoprotein [LDL (-)/L5] cholesterol is a promising biomarker for complex organ interactions and diseases associated with liver-heart axis. In this mini review, we focus not only on recent data on NAFLD mechanisms, but also on the potential of the lipid mediator LDL (-)/L5 as a diagnostic and therapeutic target for liver-heart line diseases.