| Abstract|| |
Leptin is a cytokine l6kd peptide hormone. Its crucial role is regulation of appetite and the body fat mass mainly through action on the hypothalamus. It is produced mainly in adipocytes of white fat, as well as from other tissues e.g. placenta, skeletal muscles, fundus of the stomach and activated hepatic stellate cell (HSC) and recently reported that leptin is produced from B cell of islands of the pancreas. The gene responsible for production is present on chromosome 7 called obse gene (ob/gene). Leptin receptors (OB-R) were present in two forms short (OB-Ra or OB-RS) and long one (OB-Rb or OB-RI). The main action of leptin depends on long form (OB-Rl), where very little evidence is available implicating a role for the short form in the action of leptin. One of the unconventional areas in which leptin is now receiving great attention is liver diseases as several published studies indicate that circulating leptin level are increased in cirrhosis, hepatitis C virus (HCV) and non-alcoholic steatohepatitis (NASH)
|How to cite this article:|
El-Badawy RM, Al-Ghamdi AS, Al-Mofleh IA. Concepts in leptin and liver disease. Saudi J Gastroenterol 2004;10:57-66
The name of leptin comes from the Greek word 'leptos' meaning (thin). Leptin is a cytokine 16 kd peptide product of the obse gene (ob-gene). The gene of leptin consists of 3 axons and it is located on chromosome 6 in animals (mice) and chromosome 7 in humans  . Approximately 50 years ago, two recessive mutations were discovered in obese (ob) and diabetic (db) mice and noted to result in hyperphagia, low metabolic rate, early-onset obesity and development of diabetes  . Coleman and Hummel on experiments on mouse found that the obese mouse lacks a factor and diabetic mouse is resistant to the same factor, which is now known as leptin and this is because of a mutation to its receptor and initial studies in rats suggested that the functional receptor was localized to the hypothalamus. A homozygous mutations of the (ob) gene causes absolute leptin defieciency  . The ob/ob mouse becomes hyperphagic, hypothermic, infertile and morbidly obese. Exogenous leptin replacement corrects these abnormalities and induces weight loss restricted to adipose tissue. This mutation is rare in human, and leptin therapy has only recently been shown to be efficacious in an unusual form of diabetes secondary to severe lipodystrophy .
| Physiological aspects of leptin|| |
Leptin is produced mainly in adipocytes of white fat. However, recent evidence shows that leptin can be synthesized in other tissues, e.g placenta, skeletal muscles, fundus of the stomach and activated stellate cells  . Also it is reported to be secreted from B cell of islands of pancreas . Circulating leptin after secretion is present freely as a monomar or bind to plasma protein. Although, several regulatory elements have been identified along the leptin promoter, it is unclear which of these regulatory elements are involved in transcriptional regulation related to changes in adipocytes mass  . Importantly, leptin synthesis in adipocytes is positively regulated by insulin and proinflammatory cytokines, including interleukin 1, tumour necrosis factor (TNF), Lipopolysacharides as well as steroid hormones  . The physiological actions of leptin are as follows [Figure - 1]:
- Leptin plays a key role in the control of energy balance and food intake mainly through action on the central nervous system ,
- It prevents lipid accumulation in nonadipose sites, such as the myocardium, skeletal muscle, pancreas and liver ,
- It influences the expression of several neuropeptides that regulate energy intake and expenditure as well as neuroendocrine function. It also regulate matrix deposition (fibrosis) during wound healing 
The leptin receptor (OB-R) was initially characterized from the mouse choroids plexus by means of expression cloning. At least different receptor isoform may arise from alternate splicing of OB-R messenger mRNA  . In humans, leptin receptor initially found primarily in the central nervous tissues such as hypothalamous, has also been localized to other tissues including the liver , . OB-R is a member of the haematopoietin receptor family. It is most closely related to the signal transduction subunits of the interlenkin 6 type cytokine receptor [l7] . In humans and rodents, at least 2 predominant forms of OB-R are detected. Both isoforms have identical extracellular domains and ligand binding family but differ in the intracellular domains which represent alternative splice product , . The major OB-R short form (OB-Rs or OB-R1 or OB-Ra) a 34-amino acid cytoplasmic domain, is found in many organs. However, despite normal Ligandbinding activity OB-Rs is considered incapable of signaling and very little evidence is available in implicating a role for the short form of OB-Rs in the action of leptin ,, . In contrast, the long form (OBRl or OB-R2 or OB-Rb) is the signaling competent receptor isoform and contains a 302-amino acid cytoplasmic domain  . Reverse transciption polymerase chain reaction (RT-PCR) and ribonuclease protection analysis (RPA) show that various peripheral organs, including the liver have detectable levels of mRNA encoding OBR2, implying that leptin has the potential to stimulate liver cells .
| Pathological actions of leptin|| |
Leptin signaling is mediated by the leptin receptor (OB-R), binding of leptin to OB-R induces receptor dimerization and activate the janus kinase signal transducer and activator of transcription (STAT) pathway resulting in phosphorylation of STAT proteins ..
Different STATs (STAT3 & STAT5) may be recruited to the OB-R2 receptor doking domain in various tissues, including their phosphorylation, translocation to the nucleus and binding to specific response elements resulting in transcription of target genes e.g. transforming growth factor B 1, (TGFB 1) and F 1 collagen  . The signaling effect of leptin usually results in events within minutes not hours  .
Emerging evidence would suggest that leptin could act through other signaling cascades, including the family of mitogenactivated protein kinases and the strike activated protein kinases , , that could explain the persistent increase in collagen gene activation and expression by leptin in hepatic stellate cells (HSC's)  . Recently, production of leptin from extra adipose tissue organs and expression of functional leptin receptors in various organs means that leptin regulates diversified biological functions in these organs  .
| Circulating leptin level|| |
In normal humans, the circulating level of leptin is higher in women than in men and leptin production from fat cells is affected by glucose and fat metabolism. Circulating leptin is not static reflection of body fat stores as leptin expression and secretion are affected by actual metabolic and physiological signals. Concentration decreases with fasting and increase with food consumption moreover, there may be a circadian rhythm. However, Shirakumar et al, reported that there was statistical significant difference in leptin level between men and women matched for age and sex and the mean value was as follow respectively (7.2+4.1) and (15+8.2) ng/mL .
| Leptin and its relation to liver disease|| |
One of the unconventional area in which leptin is now receiving great attention is liver diseases as several published studies have indicated that the circulating leptin levels are increasing in cirrhosis and chronic liver injury (30)
1. Non-alcoholic fatty liver disease and leptin
Non-alcoholic fatty liver disease (NAFLD) that range from simple fatty infiltration of liver cell by fat (steatosis) to steatohepatitis (a condition accompanied by inflammation and necrosis) has become a worldwide problem. Sequence of events that leads to steatosis and steatohepatitis is uncertain. Factors associated with steatosis include hyperinsulinemia, hyperglycemia, increase in expression of TNF and uncoupling protein-2 (UCP2) in adipose tissue and liver  . Normally leptin has antisteatotic effect in the liver by lowering expression of steatoregulatory element-binding protein1 (SREBP 1). This upregulates genes promoting fatty acid B-oxidation and thermogenesis, so down regulate the opposite involved in lipogenesis ,. However, insulin increases the expression of SREBP 1 so increases steatosis. Shirakumar et al, have noted a direct correlation between the severity of hepatic steatosis and leptin level but not with inflammation or fibrosis that mean failure of antisteatotic action of leptin (peripheral leptin resistance)  .
Circulating leptin is increased in both men and women with NASH and that together with serum C-peptide and age, are independent (positive) predictor of the severity of hepatic steatosis  . It is also important to note that serum total leptin level may not correlate closely with the biological action of leptin in the liver. The latter also depends on protein binding (free levels hormone), local production (autocrine and procrine effect) and number of functionally active receptors , . Several factors could contribute to the increased serum leptin levels in NASH. First, hyperleptinemia occurs in inflammatory disorder and has been attributed to cytokines such as TNF, which is also increased in NASH. Second, hyperinsulinemia, especially chronic hyperinsulinemia is associated with persistent hyperleptinemia in NASH. Third, the finding that leptin also correlates with serum C-peptide is consistent with an association between leptin and insulin resistance , . It also pertinent to reiterate that serum leptin in NASH could not be attributed simply to the presence or absence of diabetes and influence of TNF  . The present observation that serum leptin is one of only three independent predictors of hepatic steatosis in NASH is novel and intriguing  . Steatosis is a feature of clinical states characterized by defective leptin signaling. Thus, steatosis is often present in obese individuals who are generally leptin resistant  and also in patients with congenital generalized lipodystrophy, a syndrome of leptin deficiency  . The relationship between leptin and steatosis is particularly striking in the latter disorder; florid hepatic steatosis develops as early as 19 months of age and can be reversed by leptin therapy  . The finding that leptin is an independent positive predictor of the severity of hepatic steatosis in NASH is inconsistent with a simple antisteatotic effect of leptin, assuming that serum leptin values correlate with leptin biological activity in hepatocytes. The two most likely explanations are that leptin is inextricably related to insulin resistance, either causing or resulting from it (as could be interpreted from the relationship between serum leptin and C-peptide) or that patients who develop NASH differ from obese individuals who do not develop NASH by having a state of peripheral (hepatic) leptin resistance  . In relation to leptin resistance, leptin achieves its anti lipogenic effect in the liver by lowering expression of hepatic SREBP- 1. Sustained overexpression of SREBP-1 (by insulin resistance or other mechanisms) facilitates steatosis  .
A direct correlation between serum leptin level and age has been elucidated. Age was also identified as an independent predictor of steatosis  . Although the etiopathogenic significance of this is less clear, it is worth noting that mature rats become increasingly leptin resistant. An earlier study showed that, compared with that of young rats, the leptin-resistant state of older animals is marked by failure to up-regulate the enzymes involved in fatty acid oxidation (acylco-oxidase, carnitine and palmitoyl transferase 1), possibly because of the associated diminution of upregulation of the transcription factor eroxisome proliferators activated receptor 4 , . There are not yet data to form a basis upon which this finding can be extrapolated to humans, but it raises the possibility that interactive effects of age and leptin could facilitate abdominal adiposity and enhance hepatic steatosis in patient with NASH  .
Non-alcoholic liver disease is a common worldwide problem. In their study, Alba et al, concluded that elevated leptin are associated with more advanced fibrosis in patients with NAFLD and this association has been independent of the degree of insulin resistance or other potential confounders  . So therapeutic approaches that reduce leptin levels are in development and well undoubtedly be tested to determine their effectiveness in preventing or reversing hepatic fibrosis.
2.Leptin and hepatic fibrosis
Regardless of etiologies, progression of hepatic fibrosis is a major and common problem in chronic liver diseases. The relationship of serum level of leptin and hepatic fibrosis were studied by many investigators, the results confirmed the absolute requirement of leptin for hepatic fibrosis in chronic liver injury, by its action on mediators for TNFα, TGFB1 and α-1 collagen  . Leptin augments both proinflammatory and profibrogenic responses induced by acute (carbon tetrachloride) CCL4 through up-regulation of TGFB  , that is one of the key cytokines of tissue repair and fibrogenesis in the liver. Leptin enhances procollagen mRNA that reflect the synthesis of type 1 collagen in liver. However, Ikejima and his group noticed that steady-state mRNA levels of HSP47 (hot stock protein) were increased by simultaneous injection of CCL4 and leptin. HSP47 has been shown to play a pivotal role in the maturation of collagen fibrils and increases during hepatic fibrogenesis induced by various fibrogenic stimuli including CCL4 and bile duct ligation , In addition, leptin enhances the expression of smooth muscle antibodies (SMA), a hallmark of stellate cell transactivation after the potentiation of TGF 1 mRNA in the liver after CCL4 administration. A consequence of augmented pro inflammatory responses caused by leptin and CCL4 on the other hand, sinusoidal endothelial cell express functional OB-R through which leptin increase TGF 1 mRNA in these cells through upregulation of TGF  . These findings may account for - the relationship between obesity, steatosis and progression of chronic liver diseases.
Recently, obesity has been recognized as a risk factor of the development of chronic liver diseases caused by a variety of etiologies including chronic hepatitis C, alcohol and NAFLD  . Although these conditions have been associated with high serum leptin level, progression of liver fibrosis including cryptogenic cirrhosis is observed often in overweight individuals without any recognizable etiologies ,,,. The exact role of leptin in the development of NAFLD needs to be elucidated. Ikejima et al, have shown a causal link between leptin and fibrogenesis in the liver, suggesting that leptin may be one of the pathogenesis factors for hepatic inflammation and fibrogenesis in patients with NAFLD  . However, Saxena et al, have provided novel mechanisms whereby leptin affects liver fibrogenesis. Other genes associated with liver fibrosis (e.g. tissue inhibitors of metalloproteinases) are currently being studied to determine whether leptin alters their expression and in turn acts as a profibrogenic in the liver microenvironment. These data have potential implications for clarifying the mechanism of fibrosis in diseases in which circulating leptin levels are elevated such as NASH and type 2 diabetes mellitus and alcoholic cirrhosis , . Pictae et al, have observed an associated relation between high circulating leptin levels and fatigue in chronic HCV  . However, Crespo et al, have reported association between plasma leptin and TNFα levels in HCV patients and the relationship to hepatic fibrosis. Leptin has no role in determining severity of steatosis and fibrosis in patients with HCV[ 51] . Potter and Mezey, have studied the relation between leptin and schistosomal fibrosis and have conclude that leptin is a potentiating but an essential factor for the development of hepatic fibrosis  . They also have concluded that leptin deficiency reduces but does not prevent the development of hepatic fibrosis. The role of leptin in anorexia associated with liver cirrhosis remains controversial. A study by Ben and his group, reported that the, mean serum leptin level was significantly lower in the primary biliary cirrhosis group (PBC) compared to both control and hepatocellular groups  . The study revealed that serum leptin level strongly correlated with body mass index in hepatocellular group and the controls but not in the PBC group. The combined finding of normal insulin responses and less insulin resistance can lower serum leptin level in PBC compared to hepatocellular liver disease and indicate that serum leptin is merely a passive marker and not a cause of anorexia in liver disease.
3. Leptin and gallbladder disease
A study about a relationship of serum leptin concentration and other measures of adiposity with gallbladder disease was conducted by Constance and James. They evaluated the possibility of leptin which is highly correlated with total body fat mass that might be a better predictor of gall bladder disease than BMI. This did not prove to be the case because serum leptin concentration was not associated with gallbladder disease independently of BMI. The possible explanation for the lack of association of leptin concentration with gallbladder disease is that gallstone risk may be more closely related to certain fat depot, such as intra abdominal (Visceral) fat, than to total fat mass  . Another possible explanation for the lack of an independent relationship of leptin concentration with gallbladder disease is that a single leptin measurement, which is influenced by short-term energy inbalance as well as serum levels of several cytokines and hormones that show ultradian and circadian variation, does not reflect long term exposures. Although the current study cannot totally exclude leptin as a risk factor for gallbladder disease, it appear unlikely that it is a major mediator for the relationship of adiposity and gallbladder disease ,,.
4. Leptin and other liver diseases
Inverse relationship was found between circulating level of leptin and bone mineral density in patients with chronic liver disease. The reason for those findings was uncertain but a pathophysiological role of circulating leptin is possible  . Campillo et al, studied serum leptin levels in alcoholic liver cirrhosis and concluded that there is a gender difference in regulation of serum leptin level increasing more in male patients  . However, in a study done by Nakamuta about serum leptin level in nonalcoholic patients showed that, the serum leptin level of patients with non-alcoholic liver diseases was not elevated. On the other hand, the serum leptin level of patients with alcoholic cirrhosis has been reported to be elevated. The difference in the serum leptin level of patients with nonalcoholic liver disease and that of patients with alcoholic cirrhosis may be due to difference in factors such as the level of cytokines or sex steroids and/or nutrition. Furthermore, it is likely that leptin is cleared in part by the portosystemic circulation through the liver .
| Leptin effect on other organs|| |
Park et al, reported that leptin has potential role in angiogenesis, through induction of endolethial cell proliferation and expression of matrix metalloproteinases in vivo and vitro  . However, it is not clear how leptin works to promote multi-step processes involved in the neovascularization at the atherosclerotic plaque. Immunohistochemical analysis of human atherosclerotic aorta revealed an increased expression of OB-R in the intima of neorevascularized regions and of both matrix metalloprotienase (MMPs) and tissue inhibitor metalloproteinase (TIMPs) predominantly in the endolethial lining of intimal neovessels and macrophages/foam cells. Leptin (10-40 ng/ml) induced proliferation of human umbilical veins endothelial cells (HUVECs) and elevation of MMP-2, MMP-9, TsMP-5, TsMP-2 expression in a dose-dependent manner. Leptin also induced increases of MMP-2, MMP4, T1MP-1 and upregulated the human coronary artery smooth muscle cells. These findings suggest that leptin, a hormone with pluralistic properties including a mitogenic activity on vascular endothelial cells, play a role in matrix remodeling by regulating the expression of MMPs and T1MPs.
Diabetes mellitus (DM):
Several recent reports have implicated leptin as a critical hormone in the development of fibrosis in general, as well as its role in wound healing and remodeling. However, a study done by Gariano and his group showed that leptin can induce cell proliferation as well as augment collagen gene expression, leading to diabetic ophthalmopathy and glomerulosclerosis 
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Reda Mohammed El-Badawy
Department of Hepatology and Gastroenterology, Benaha University Hospital, Farid Nada St. Kalubia, Egypt
Source of Support: None, Conflict of Interest: None
[Figure - 1]