The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver in combination with metabolic dysfunction in the form of overweight or obesity and insulin resistance. It is also associated with an increased cardiovascular disease risk, including hypertension and atherosclerosis. Hepatic lipid metabolism is regulated by a combination of the uptake and export of fatty acids, de novo lipogenesis, and fat utilization by β-oxidation. When the balance between these pathways is altered, hepatic lipid accumulation commences, and long-term activation of inflammatory and fibrotic pathways can progress to worsen the liver disease. This review discusses the details of the molecular mechanisms regulating hepatic lipids and the emerging therapies targeting these pathways as potential future treatments for MAFLD.

Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene transcription by nuclear receptors. Studies are now revealing that low plasma bilirubin levels, defined as “hypobilirubinemia,” are a possible new pathology analogous to the other end of the spectrum of extreme hyperbilirubinemia seen in patients with jaundice and liver dysfunction. Hypobilirubinemia is most commonly seen in patients with metabolic dysfunction, which may lead to cardiovascular complications and possibly stroke. We address the clinical significance of low bilirubin levels. A better understanding of bilirubin’s hormonal function may explain why hypobilirubinemia might be deleterious. We present mechanisms by which bilirubin may be protective at mildly elevated levels and research directions that could generate treatment possibilities for patients with hypobilirubinemia, such as targeting of pathways that regulate its production or turnover or the newly designed bilirubin nanoparticles. Our review here calls for a shift in the perspective of an old molecule that could benefit millions of patients with hypobilirubinemia.

Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against cardiovascular and metabolic diseases such as obesity and diabetes. Bilirubin is a potent antioxidant, and the beneficial actions of moderate increases in plasma bilirubin have been thought to be due to the antioxidant effects of this bile pigment. In the present study, we found that bilirubin has a new function as a ligand for PPARα. We show that bilirubin can bind directly to PPARα and increase transcriptional activity. When we compared biliverdin, the precursor to bilirubin, on PPARα transcriptional activation to known PPARα ligands, WY 14,643 and fenofibrate, it showed that fenofibrate and biliverdin have similar activation properties. Treatment of 3T3-L1 adipocytes with biliverdin suppressed lipid accumulation and upregulated PPARα target genes. We treated wild-type and PPARα KO mice on a high fat diet with fenofibrate or bilirubin for seven days and found that both signal through PPARα dependent mechanisms. Furthermore, the effect of bilirubin on lowering glucose and reducing body fat percentage was blunted in PPARα KO mice. These data demonstrate a new function for bilirubin as an agonist of PPARα, which mediates the protection from adiposity afforded by moderate increases in bilirubin.

Glucocorticoid hormones (GCs) are important regulators of lipid metabolism, promoting lipolysis with acute treatment but lipogenesis with chronic exposure. Conventional wisdom posits that these disparate outcomes are mediated by the classical glucocorticoid receptor GRα. There is insufficient knowledge of the GC receptors (GRα and GRβ) in metabolic conditions such as obesity and diabetes. We present acute models of GC exposure that induce lipolysis, such as exercise, as well as chronic-excess models that cause obesity and lipid accumulation in the liver, such as hepatic steatosis. Alternative mechanisms are then proposed for the lipogenic actions of GCs, including induction of GC resistance by the GRβ isoform, and promotion of lipogenesis by GC activation of the mineralocorticoid receptor (MR). Finally, the potential involvement of chaperone proteins in the regulation of adipogenesis is considered. This reevaluation may prove useful to future studies on the steroidal basis of adipogenesis and obesity.