Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors.The worldwide prevalence of obesity and associated cardiometabolic diseases have increased dramatically in the past 2-3 decades, rapidly becoming major challenges to the health care systems of most industrialized countries. Current estimates indicate that Ͼ1 billion people in the world are overweight or obese (1). In the United States, at least 65% of adults are overweight, and approximately one-third of adults are obese with a body mass index (defined as kilograms of weight/m 2 of height) of Ͼ30 (2). In children, the prevalence of obesity has also risen rapidly in parallel with increasing obesity in adults; a recent report indicates that 18.4% of 4-year-old children in the United States are obese, with significantly higher rates of obesity in Hispanic, black, and Native American children (3).Associated with obesity is a cascade of metabolic and cardiovascular disorders, including hypertension, a primary mediator of obesity-induced cardiovascular disease. Population studies show that excess weight gain predicts future development of hypertension, and the relationship between body mass index and blood pressure (BP) 2 appears to be nearly linear in diverse populations throughout the world (4). Some studies suggest that excess weight gain may account for 65-75% of human essential hypertension (5). Moreover, clinical studies indicate that weight loss is effective in primary prevention of hypertension and in reducing BP in most hypertensive subjects (6).Although the importance of obesity as a major cause of essential hypertension is well established, the physiological and molecular mechanisms that mediate the BP effects of excess weight gain are only beginning to be elucidated. Excess Weight Gain Increases Renal SodiumReabsorption and Impairs Pressure Natriuresis Table 1 summarizes some of the changes in cardiovascular, neurohormonal, and renal function that occur in obese humans and experimental animals (4,7,8). Notable changes, in addition to increased BP, include increases in cardiac output and heart rate as well as activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS). Rapid weight gain also stimulates renal tubular sodium reabsorption, and obese subjects require higher than normal BP to maintain balance between intake and renal excretion of sodium, indicating impaired renal pressure natriuresis (4).Three factors are especially important in increasing re...

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.

Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin levels are reflective of liver disease due to an injurious effect on hepatocytes. In healthy liver, bilirubin is conjugated and excreted to the intestine and converted by microbes to urobilinoids, which are reduced to the predominant pigment in feces, stercobilin, or reabsorbed. The function of urobilinoids in the gut or their physiological relevance of reabsorption is not well understood. In this review, we discuss the relationship of hepatic bilirubin signaling to the intestinal microbiota and its regulation of the liver-gut axis, as well as its capacity to mediate these processes.

Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, ultimately resulting in liver cirrhosis and failure. Biliverdin reductase A (BVRA) is a multifunctioning protein primarily responsible for the reduction of biliverdin to bilirubin. Also, BVRA functions as a kinase and transcription factor, regulating several cellular functions. We report here that liver BVRA protects against hepatic steatosis by inhibiting glycogen synthase kinase 3β (GSK3β) by enhancing serine 9 phosphorylation, which inhibits its activity. We show that GSK3β phosphorylates serine 73 (Ser(P)) of the peroxisome proliferator-activated receptor α (PPARα), which in turn increased ubiquitination and protein turnover, as well as decreased activity. Interestingly, liver-specific BVRA KO mice had increased GSK3β activity and Ser(P) of PPARα, which resulted in decreased PPARα protein and activity. Furthermore, the liver-specific BVRA KO mice exhibited increased plasma glucose and insulin levels and decreased glycogen storage, which may be due to the manifestation of hepatic steatosis observed in the mice. These findings reveal a novel BVRA-GSKβ-PPARα axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease.

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.