Non-Alcoholic Fatty Liver Disease in Lean and Non-Obese Individuals: Current and Future Challenges - PubMed (original) (raw)
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Non-Alcoholic Fatty Liver Disease in Lean and Non-Obese Individuals: Current and Future Challenges
Mohammad Shafi Kuchay et al. Biomedicines. 2021.
Abstract
Non-alcoholic fatty liver disease (NAFLD), which approximately affects a quarter of the world's population, has become a major public health concern. Although usually associated with excess body weight, it may also affect normal-weight individuals, a condition termed as lean/non-obese NAFLD. The prevalence of lean/non-obese NAFLD is around 20% within the NAFLD population, and 5% within the general population. Recent data suggest that individuals with lean NAFLD, despite the absence of obesity, exhibit similar cardiovascular- and cancer-related mortality compared to obese NAFLD individuals and increased all-cause mortality risk. Lean and obese NAFLD individuals share several metabolic abnormalities, but present dissimilarities in genetic predisposition, body composition, gut microbiota, and susceptibility to environmental factors. Current treatment of lean NAFLD is aimed at improving overall fitness and decreasing visceral adiposity, with weight loss strategies being the cornerstone of treatment. Moreover, several drugs including PPAR agonists, SGLT2 inhibitors, or GLP-1 receptor agonists could also be useful in the management of lean NAFLD. Although there has been an increase in research regarding lean NAFLD, there are still more questions than answers. There are several potential drugs for NAFLD therapy, but clinical trials are needed to evaluate their efficacy in lean individuals.
Keywords: gut microbiota; insulin resistance; lean NAFLD; metabolic syndrome; visceral adiposity.
Conflict of interest statement
M.S.K. has received speaker honoraria from Sanofi, Wockhardt Limited, Novo Nordisk, Novartis, and AstraZeneca. J.C.F.-G. has received speaker honoraria from Sanofi, Novo Nordisk, Lilly, Boehringer-Ingelheim, Mundipharma, Esteve, and AstraZeneca. J.I.M.-M., N.S.C. and B.R.-M. have nothing to declare.
Figures
Figure 1
Pathophysiology of NAFLD in lean individuals. In genetically predisposed (PNPLA3, TM6SF2) lean or non-obese individuals, free fatty acids (FFAs), mainly derived from the visceral adipose tissue, are taken up by the liver. Hepatic FFA accumulation can be influenced by the presence of insulin resistance, dysfunctional adiposity, and/or and lifestyle habits (unhealthy diets, physical inactivity). Excess of dietary sugars (glucose, fructose) are converted into FFAs by de novo lipogenesis (DNL). FFAs in the liver mitochondria undergo β-oxidation or are converted back into triglycerides (TGs) for export to the circulation via VLDL. Overwhelming of FFA disposal mechanisms leads to accumulation of TGs as lipid droplets in the hepatocytes (non-alcoholic fatty liver; NAFL). When the FFA pool expands further, cytotoxic lipid species (e.g., LPCs, DAGs, and ceramides) are produced, which ultimately mediate oxidative stress, endoplasmic reticulum (ER) stress, and inflammasome activation. These pathological processes lead to hepatocellular injury, inflammatory cell recruitment, and apoptosis/necroptosis to produce the histological phenotype of non-alcoholic steatohepatitis (NASH). Major modulators of the hepatocellular response to lipotoxic stress may include the gut microbiota products; a variety of cytokines, chemokines, and adipokines; free cholesterol; uric acid; and possibly periodic hypoxia caused by obstructive sleep apnea. Overinduction of inflammatory processes then stimulates hepatic stellate cells (HSC) and activates fibrogenesis. HSC activation is the final common pathway for a diverse group of signals, such as transforming growth factor-beta (TGF-β), platelet-derived growth factor-beta (PDGF-β), interleukins (ILs), hedgehog ligands (Hhs), and extracellular vesicles (EVs). Increased tissue inhibitors of matrix metalloproteinases (TIMPs) cause inhibition of matrix metalloproteinases (MMPs), thereby leading to net gain of fibrosis tissue by the liver. Excessive and disorganized fibrous tissue causes disruption of hepatocellular architecture and nodule formation, leading to cirrhosis of the liver. PNPLA3, patatin-like phospholipase domain containing 3; TM6SF2, Transmembrane 6 superfamily 2; CETP, Cholesteryl ester transfer protein; SREBF-2, sterol regulatory element binding transcription factor 2; LPCs, lysophosphatidylcholines; DAGs, diacyl glycerols; PMNs, polymorphonuclear leucocytes; NKTs, natural killer T cells; Tregs, regulatory T cells.
Figure 2
Individuals with lean and non-obese NAFLD have an intermediate phenotype between healthy (lean non-NAFLD) and obese NAFLD subjects. Lean is defined as body mass index (BMI) < 25 kg/m2 in Caucasians and <23 kg/m2 in Asians. Non-obese is defined as BMI < 30 kg/m2 in Caucasians and <25 kg/m2 in Asians. Obese NAFLD is defined as BMI ≥ 25 kg/m2 in Asians and ≥30 kg/m2 in Caucasians. NAFLD, non-alcoholic fatty liver disease; CV, cardiovascular.
References
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