In the past few decades, non-alcoholic fatty liver disease (NAFLD) and heart failure with preserved ejection fraction (HFpEF) have become the most common chronic liver disease and the main form of heart failure (HF), respectively. NAFLD is closely associated with HFpEF by sharing common risk factors and/or by boosting systemic inflammation, releasing other secretory factors, and having an expansion of epicardial adipose tissue (EAT). Therefore, the treatments of NAFLD may also affect the development and prognosis of HFpEF. However, no specific drugs for NAFLD have been approved by the Food and Drug Administration (FDA) and some non-specific treatments for NAFLD are applied in the clinic. Currently, the treatments of NAFLD can be divided into non-pharmacological and pharmacological treatments. Non-pharmacological treatments mainly include dietary intervention, weight loss by exercise, caloric restriction, and bariatric surgery. Pharmacological treatments mainly include administering statins, thiazolidinediones, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, and metformin. This review will mainly focus on analyzing how these treatments may affect the development and prognosis of HFpEF.

The increased burden of nonalcoholic fatty liver disease (NAFLD) parallels the increased incidence of overweight and metabolic syndrome worldwide. Because of the close relationship between metabolic disorders and fatty liver disease, a new term, metabolic-related fatty liver disease (MAFLD), was proposed by a group of experts to more precisely describe fatty liver disease resulting from metabolic disorders. According to the definitions, MAFLD and NAFLD populations have considerable discrepancies, but overlap does exist. This new definition has a nonnegligible impact on clinical practices, including diagnoses, interventions, and the risk of comorbidities. Emerging evidence has suggested that patients with MAFLD have more metabolic comorbidities and an increased risk of all-cause mortality, particularly cardiovascular mortality than patients with NAFLD. In this review, we systemically summarized and compared the risk and underlying mechanisms of cardiovascular disease (CVD) in patients with NAFLD or MAFLD.

BackgroundPathological cardiac hypertrophy is commonly resulted from sustained pressure overload and/or metabolic disorder and eventually leads to heart failure, lacking specific drugs in clinic. Here, we aimed to identify promising anti-hypertrophic drug(s) for heart failure and related metabolic disorders by using a luciferase reporter-based high-throughput screening.MethodsA screen of the FDA-approved compounds based on luciferase reporter was performed, with identified luteolin as a promising anti-hypertrophic drug. We systematically examined the therapeutic efficacy of luteolin on cardiac hypertrophy and heart failure in vitro and in vivo models. Transcriptome examination was performed to probe the molecular mechanisms of luteolin.ResultsAmong 2,570 compounds in the library, luteolin emerged as the most robust candidate against cardiomyocyte hypertrophy. Luteolin dose-dependently blocked phenylephrine-induced cardiomyocyte hypertrophy and showed extensive cardioprotective roles in cardiomyocytes as evidenced by transcriptomics. More importantly, gastric administration of luteolin effectively ameliorated pathological cardiac hypertrophy, fibrosis, metabolic disorder, and heart failure in mice. Cross analysis of large-scale transcriptomics and drug-target interacting investigations indicated that peroxisome proliferator activated receptor γ (PPARγ) was the direct target of luteolin in the setting of pathological cardiac hypertrophy and metabolic disorders. Luteolin can directly interact with PPARγ to inhibit its ubiquitination and subsequent proteasomal degradation. Furthermore, PPARγ inhibitor and PPARγ knockdown both prevented the protective effect of luteolin against phenylephrine-induced cardiomyocyte hypertrophy in vitro.ConclusionOur data clearly supported that luteolin is a promising therapeutic compound for pathological cardiac hypertrophy and heart failure by directly targeting ubiquitin-proteasomal degradation of PPARγ and the related metabolic homeostasis.