From circadian clocks to non-alcoholic fatty liver disease

ABSTRACT

Introduction: The circadian rhythm is an integral regulator of various endocrine processes in the body, including sleep-wake cycles, hormonal regulation, and metabolism. In addition to metabolic, genetic, and environmental factors, a dysregulated circadian rhythm resulting from lifestyle changes has been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). An accumulating body of evidence also supports strong association between NAFLD and metabolic disorder, the pathogenesis of which is related to periodic fluctuations in hormonal homeostasis. It is clear that endocrine and circadian rhythms are tightly interconnected. Generally, the circadian rhythm regulates flux patterns of physiological functions. The present review will discuss the modulation of bodily processes by the circadian rhythm with specific attention to the regulation of NAFLD by leptin and related hormones.

Areas covered: PubMed/MEDLINE was searched for articles related to concomitant occurrence of NAFLD and T2DM between January 1995 and September 2019. Areas covered included epidemiological, physiology and pathophysiology aspects.

Expert opinion: NAFLD and NASH are increasingly prevalent and may be largely mitigated with effective lifestyle modification and, potentially, circadian rhythm stabilization. Improved knowledge of the specific pathogenesis of NAFLD in addition to enhanced diagnostic screening tools and prediction of future disease burden is imperative.

KEYWORDS:

• Circadian clocks
• NAFLD
• leptin
• melatonin
• metabolic syndrome

Article highlights

• 1. The pathogenesis of NAFLD is multi-factorial and includes metabolic risk factors, an accumulating body of evidence supports strong association between NAFLD and metabolic disorder, the pathogenesis of which is related to periodic fluctuations in hormonal homeostasis.

• 2. Secretion of leptin from adipocytes displays a circadian rhythm, circadian clock disruption may lead to abnormal secretion of leptin and the development of NAFLD .In leptin-deficient mice, the circadian clock genes Clock, were significantly repressed in obese and diabetic mice.

• 3. Disruptions to the circadian clock are linked to irregular lipid metabolism through leptin resistance and ER stress in the hypothalamus. It is likely that these changes in the circadian rhythm are also associated with metabolic syndrome and NAFLD.

• 4. In addition to leptin, hormones such as melatonin, glucocorticoids, adiponectin, human resistin may also participate in the progression of NAFLD due to circadian clocks changes.

• 5. There is already evidence that circadian rhythm changes may lead to the development of NAFLD, but much research is still needed to elucidate the molecular pathway of NAFLD, this may provide direction for future research and treatment.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported in part by the Science and Technology Plan of Beijing Tongzhou District. (KJ2019CX012-38, KJ2019CX014-29).