Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis

Nonalcoholic fatty liver disease (NAFLD) is characterized by lipotoxicity and ectopic lipid deposition within hepatocytes. Sulforaphane (SFA), an active compound used for inhibiting tumors, was found to have the potency to improve lipid metabolism. However, its molecular mechanisms on ameliorating NAFLD are still incompletely understood. This research evaluated if SFA could inhibit hepatic steatosis and apoptosis. The effects of SFA on cell viability, lipid accumulation, triglyceride (TG) contents, apoptosis, ceramide contents, and reactive oxygen species (ROS) levels were analyzed in palmitic acid (PA)-treated HepG2 cells and high-fat diet (HFD)-fed mice. The related molecular mechanisms were further explored in hepatocytes. The results showed SFA alleviated lipid accumulation and regulated AMPK/SREBP1c/FAS signaling pathway in PA-stressed HepG2 cells. In addition, SFA alleviated PA-mediated apoptosis, downregulated the expressions of cleaved caspase 3, as well as reduced ceramide contents and ROS levels. Moreover, SFA treatment reduced HFD-induced body weight gain, alleviated insulin resistance, decreased serum TG, total cholesterol (TC), and alanine aminotransferase (ALT) levels, and prevented lipid deposition and apoptosis in the liver. This study showed SFA suppressed lipid deposition and apoptosis both in vitro and in vivo, indicating that SFA may be a potential candidate for preventing and treating NAFLD.

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Dynamics of hepatic steatosis resolution and changes in gut microbiome with weight loss in nonalcoholic fatty liver disease

Obesity Science & Practice ◽

10.1002/osp4.476 ◽

2021 ◽

Author(s):

Jaideep Behari ◽

Lisa Graham ◽

Renwei Wang ◽

Claudiu Schirda ◽

Amir A. Borhani ◽

...

Keyword(s):

Weight Loss ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Steatosis ◽

Gut Microbiome ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver

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Dissociation of hepatic insulin resistance from susceptibility of nonalcoholic fatty liver disease induced by a high-fat and high-carbohydrate diet in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00291.2013 ◽

2014 ◽

Vol 306 (6) ◽

pp. G496-G504 ◽

Cited By ~ 18

Author(s):

Akihiro Asai ◽

Pauline M. Chou ◽

Heng-Fu Bu ◽

Xiao Wang ◽

M. Sambasiva Rao ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Diet Group ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Akt Phosphorylation ◽

High Carbohydrate

Liver steatosis in nonalcoholic fatty liver disease is affected by genetics and diet. It is associated with insulin resistance (IR) in hepatic and peripheral tissues. Here, we aimed to characterize the severity of diet-induced steatosis, obesity, and IR in two phylogenetically distant mouse strains, C57BL/6J and DBA/2J. To this end, mice (male, 8 wk old) were fed a high-fat and high-carbohydrate (HFHC) or control diet for 16 wk followed by the application of a combination of classic physiological, biochemical, and pathological studies to determine obesity and hepatic steatosis. Peripheral IR was characterized by measuring blood glucose level, serum insulin level, homeostasis model assessment of IR, glucose intolerance, insulin intolerance, and AKT phosphorylation in adipose tissues, whereas the level of hepatic IR was determined by measuring insulin-triggered hepatic AKT phosphorylation. We discovered that both C57BL/6J and DBA/2J mice developed obesity to a similar degree without the feature of liver inflammation after being fed an HFHC diet for 16 wk. C57BL/6J mice in the HFHC diet group exhibited severe pan-lobular steatosis, a marked increase in hepatic triglyceride levels, and profound peripheral IR. In contrast, DBA/2J mice in the HFHC diet group developed only a mild degree of pericentrilobular hepatic steatosis that was associated with moderate changes in peripheral IR. Interestingly, both C57BL/6J and DBA/2J developed severe hepatic IR after HFHC diet treatment. Collectively, these data suggest that the severity of diet-induced hepatic steatosis is correlated to the level of peripheral IR, not with the severity of obesity and hepatic IR. Peripheral rather than hepatic IR is a dominant factor of pathophysiology in nonalcoholic fatty liver disease.

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Reproductive Endocrinology of Nonalcoholic Fatty Liver Disease

Endocrine Reviews ◽

10.1210/er.2018-00158 ◽

2018 ◽

Vol 40 (2) ◽

pp. 417-446 ◽

Cited By ~ 16

Author(s):

Mathis Grossmann ◽

Margaret E Wierman ◽

Peter Angus ◽

David J Handelsman

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Energy Homeostasis ◽

Sex Hormone Binding Globulin ◽

Sex Steroid ◽

Receptor Signaling ◽

Nonalcoholic Fatty Liver

Abstract The liver and the reproductive system interact in a multifaceted bidirectional fashion. Sex steroid signaling influences hepatic endobiotic and xenobiotic metabolism and contributes to the pathogenesis of functional and structural disorders of the liver. In turn, liver function affects the reproductive axis via modulating sex steroid metabolism and transport to tissues via sex hormone–binding globulin (SHBG). The liver senses the body’s metabolic status and adapts its energy homeostasis in a sex-dependent fashion, a dimorphism signaled by the sex steroid milieu and possibly related to the metabolic costs of reproduction. Sex steroids impact the pathogenesis of nonalcoholic fatty liver disease, including development of hepatic steatosis, fibrosis, and carcinogenesis. Preclinical studies in male rodents demonstrate that androgens protect against hepatic steatosis and insulin resistance both via androgen receptor signaling and, following aromatization to estradiol, estrogen receptor signaling, through regulating genes involved in hepatic lipogenesis and glucose metabolism. In female rodents in contrast to males, androgens promote hepatic steatosis and dysglycemia, whereas estradiol is similarly protective against liver disease. In men, hepatic steatosis is associated with modest reductions in circulating testosterone, in part consequent to a reduction in circulating SHBG. Testosterone treatment has not been demonstrated to improve hepatic steatosis in randomized controlled clinical trials. Consistent with sex-dimorphic preclinical findings, androgens promote hepatic steatosis and dysglycemia in women, whereas endogenous estradiol appears protective in both men and women. In both sexes, androgens promote hepatic fibrosis and the development of hepatocellular carcinoma, whereas estradiol is protective.

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Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22189969 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9969

Author(s):

Mariano Schiffrin ◽

Carine Winkler ◽

Laure Quignodon ◽

Aurélien Naldi ◽

Martin Trötzmüller ◽

...

Keyword(s):

Gene Expression ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Liver Steatosis ◽

Whole Body ◽

Sex Dimorphism ◽

Nonalcoholic Fatty Liver

Men with nonalcoholic fatty liver disease (NAFLD) are more exposed to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of NALFD sex dimorphism are unclear. We combined gene expression, histological and lipidomic analyses to systematically compare male and female liver steatosis. We characterized hepatosteatosis in three independent mouse models of NAFLD, ob/ob and lipodystrophic fat-specific (PpargFΔ/Δ) and whole-body PPARγ-null (PpargΔ/Δ) mice. We identified a clear sex dimorphism occurring only in PpargΔ/Δ mice, with females showing macro- and microvesicular hepatosteatosis throughout their entire life, while males had fewer lipid droplets starting from 20 weeks. This sex dimorphism in hepatosteatosis was lost in gonadectomized PpargΔ/Δ mice. Lipidomics revealed hepatic accumulation of short and highly saturated TGs in females, while TGs were enriched in long and unsaturated hydrocarbon chains in males. Strikingly, sex-biased genes were particularly perturbed in both sexes, affecting lipid metabolism, drug metabolism, inflammatory and cellular stress response pathways. Most importantly, we found that the expression of key sex-biased genes was severely affected in all the NAFLD models we tested. Thus, hepatosteatosis strongly affects hepatic sex-biased gene expression. With NAFLD increasing in prevalence, this emphasizes the urgent need to specifically address the consequences of this deregulation in humans.

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Potential Natural Compounds for the Prevention and Treatment of Nonalcoholic Fatty Liver Disease: A Review on Molecular Mechanisms

Current Molecular Pharmacology ◽

10.2174/1874467215666211217120448 ◽

2021 ◽

Vol 15 ◽

Author(s):

Cheng Ma ◽

Cheng Wang ◽

Yafang Zhang ◽

Honglin Zhou ◽

Yunxia Li

Keyword(s):

Liver Disease ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Natural Compounds ◽

Nonalcoholic Fatty Liver ◽

Prevention And Treatment

Background: Nonalcoholic fatty liver disease (NAFLD) is a kind of metabolic stress-induced liver injury closely related to insulin resistance and genetic susceptibility, and there is no specific drug for its clinical treatment currently. In recent years, a large amount of literature has reported that many natural compounds extracted from traditional Chinese medicine (TCM) can improve NAFLD through various mechanisms. According to the latest reports, some emerging natural compounds have shown great potential to improve NAFLD but are seldom used clinically due to the lacking special research. Purpose: This paper aims to summarize the molecular mechanisms of the potential natural compounds on improving NAFLD, thus providing a direction and basis for further research on the pathogenesis of NAFLD and the development of effective drugs for the prevention and treatment of NAFLD. Methods: By searching various online databases, such as Web of Science, SciFinder, PubMed, and CNKI, NAFLD and these natural compounds were used as the keywords for detailed literature retrieval. Results: The pathogenesis of NAFLD and the molecular mechanisms of the potential natural compounds on improving NAFLD have been reviewed. Conclusion: Many natural compounds from traditional Chinese medicine have a good prospect in the treatment of NAFLD, which can serve as a direction for the development of anti-NAFLD drugs in the future.

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Molecular Mechanisms of Nonalcoholic Fatty Liver Disease (NAFLD)/Nonalcoholic Steatohepatitis (NASH)

Advances in Experimental Medicine and Biology - Carotenoids: Biosynthetic and Biofunctional Approaches ◽

10.1007/978-981-15-7360-6_20 ◽

2021 ◽

pp. 223-229

Author(s):

Tsuguhito Ota

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Nonalcoholic Steatohepatitis ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Nonalcoholic Fatty Liver

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Protective Effect of a Mixture of Astragalus membranaceus and Lithospermum erythrorhizon Extract against Hepatic Steatosis in High Fat Diet-Induced Nonalcoholic Fatty Liver Disease Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/8370698 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Doo Jin Choi ◽

Seong Cheol Kim ◽

Gi Eun Park ◽

Bo-Ram Choi ◽

Dae Young Lee ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Density Lipoprotein ◽

Lithospermum Erythrorhizon ◽

High Fat ◽

Nonalcoholic Fatty Liver

The present study aimed to evaluate the potential synergistic and protective effects of ALM16, a mixture of Astragalus membranaceus (AM) and Lithospermum erythrorhizon (LE) extract in a ratio of 7 : 3, against hepatic steatosis in high fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) mice. Forty-eight mice were randomly divided into eight groups and orally administered daily for 6 weeks with a normal diet (ND) or high fat diet alone (HFD), HFD with AM (HFD + 100 mg/kg AM extract), HFD with LE (HFD + 100 mg/kg LE extract), HFD with ALM16 (HFD + 50, 100, and 200 mg/kg ALM16), or HFD with MT (HFD + 100 mg/kg Milk thistle extract) as a positive control. ALM16 significantly decreased the body and liver weight, serum and hepatic lipid profiles, including triglyceride (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL), and low-density lipoprotein-cholesterol (LDL), and serum glucose levels, compared to the HFD group. Moreover, ALM16 significantly ameliorated the HFD-induced increased hepatic injury markers, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and gamma-glutamyltransferase (GGT)-1. Furthermore, as compared to the mice fed HFD alone, ALM16 increased the levels of phosphorylated AMP-activated protein kinase (p-AMPK) and acetyl-CoA carboxylase (p-ACC), thereby upregulating the expression of carnitine palmitoyltransferase (CPT)-1 and downregulating the expression of sterol regulatory element-binding protein (SREBP)-1c and fatty acid synthase (FAS). These results demonstrated that ALM16 markedly inhibited HFD-induced hepatic steatosis in NAFLD mice by modulating AMPK and ACC signaling pathways, and may be more effective than the single extracts of AM or LE.

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