Inhibition of Adenosine Monophosphate–Activated Protein Kinase–3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Signaling Leads to Hypercholesterolemia and Promotes Hepatic Steatosis and Insulin Resistance

Loh, Kim; Tam, Shanna; Murray‐Segal, Lisa; Huynh, Kevin; Meikle, Peter J.; Scott, John W.; Denderen, Bryce J. van; Chen, Zhiping; Steel, Rohan; LeBlond, Nicholas D.; Burkovsky, Leah; O’Dwyer, Conor; Nunes, Julia R. C.; Steinberg, Gregory R.; Fullerton, Morgan D.; Galić, Sandra; Kemp, Bruce E.

doi:10.1002/hep4.1279

Cited by 61 publications

(51 citation statements)

References 48 publications

(97 reference statements)

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“…AMPK is a key role in regulating the balance of cell catabolism and anabolism. A previous study has indicated that AMPKα activation plays a key role in cholesterol homeostasis by inhibiting hepatic cholesterol synthesis [ 26 ]. AMPK activation can down-regulate lipogenic transcription factors PPARγ and SREBP-1c, thereby inhibiting the lipogenic genes [ 27 , 28 ].…”

Section: Resultsmentioning

confidence: 99%

Effects and Mechanisms of Chitosan and ChitosanOligosaccharide on Hepatic Lipogenesis and Lipid Peroxidation, Adipose Lipolysis, and Intestinal Lipid Absorption in Rats with High-Fat Diet-Induced Obesity

Liu

Chen

Chiang

2021

IJMS

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Chitosan and its derivative, chitosan oligosaccharide (CO), possess hypolipidemic and anti-obesity effects. However, it is still unclear if the mechanisms are different or similar between chitosan and CO. This study was designed to investigate and compare the effects of CO and high-molecular-weight chitosan (HC) on liver lipogenesis and lipid peroxidation, adipose lipolysis, and intestinal lipid absorption in high-fat (HF) diet-fed rats for 12 weeks. Rats were divided into four groups: normal control diet (NC), HF diet, HF diet+5% HC, and HF diet+5% CO. Both HC and CO supplementation could reduce liver lipid biosynthesis, but HC had a better effect than CO on improving liver lipid accumulation in HF diet-fed rats. The increased levels of triglyceride decreased lipolysis rate, and increased lipoprotein lipase activity in the perirenal adipose tissue of HF diet-fed rats could be significantly reversed by both HC and CO supplementation. HC, but not CO, supplementation promoted liver antioxidant enzymes glutathione peroxidase and superoxide dismutase activities and reduced liver lipid peroxidation. In the intestines, CO, but not HC, supplementation reduced lipid absorption by reducing the expression of fabp2 and fatp4 mRNA. These results suggest that HC and CO have different mechanisms for improving lipid metabolism in HF diet-fed rats.

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Section: Resultsmentioning

confidence: 99%

Effects and Mechanisms of Chitosan and ChitosanOligosaccharide on Hepatic Lipogenesis and Lipid Peroxidation, Adipose Lipolysis, and Intestinal Lipid Absorption in Rats with High-Fat Diet-Induced Obesity

Liu

Chen

Chiang

2021

IJMS

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“…Diets supplemented with 5% CO in HF diet-fed rats do not improve HF diet-inhibited protein expressions of phosphorylated AMPKα and PPARα ( Figure 5A and 5B). Previous studies have indicated that AMPKα as well as PPARα activation plays pivotal roles in cholesterol homeostasis by inhibiting hepatic cholesterol synthesis and promoting the cholesterol efflux capacity, respectively [21,22]. Next, we respectively evaluated the upregulated/downregulated transcriptional expressions functioned for cholesterol synthesis, LDLR, and CYP7A1, while AMPKα was activated.…”

Section: The Mechanism Of Hc Lc and Co In The Livers And Intestinesmentioning

confidence: 99%

Comparative Effects and Mechanisms of Chitosan and Its Derivatives on Hypercholesterolemia in High-Fat Diet-Fed Rats

Chiu¹,

Yen

Liu

et al. 2019

IJMS

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The present study investigated and compared the effects of different molecular weights of chitosan (high molecular weight chitosan (HC) and low molecular weight chitosan (LC)) and its derivatives (chitosan oligosaccharide (CO)) on cholesterol regulation in high-fat (HF) diet-fed rats. A diet supplementation of 5% HC, 5% LC, or 5% CO for 8 weeks showed hypocholesterolemic potential in HF diet-fed rats. Unexpectedly, a 5% CO-supplemented diet exerted hepatic damage, producing increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor-alpha (TNF-α). The supplementation of HC and LC, unlike CO, significantly decreased the hepatic total cholesterol (TC) levels and increased the fecal TC levels in HF diet-fed rats. The hepatic protein expression of the peroxisome proliferator-activated receptor-α (PPARα) in the HF diet-fed rats was markedly decreased, which could be significantly reversed by both HC and LC, but not CO, supplementation. Unlike the supplementation of CO, both HC and LC supplementation could effectively reverse the HF-inhibited/induced gene expressions of the low-density lipoprotein receptor (LDLR) and cholesterol 7α-hydroxylase (CYP7A1), respectively. The upregulated intestinal acyl-CoA cholesterol acyltransferase 2 (ACAT2) protein expression in HF diet-fed rats could be reversed by HC and LC, but not CO, supplementation. Taken together, a supplementation of 5% CO in HF diet-fed rats may exert liver damage via a higher hepatic cholesterol accumulation and a higher intestinal cholesterol uptake. Both HC and LC effectively ameliorated the hypercholesterolemia and regulated cholesterol homeostasis via the activation and inhibition of hepatic (AMPKα and PPARα) and intestinal (ACAT2) cholesterol-modulators, respectively, as well as the modulation of downstream signals (LDLR and CYP7A1).

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“…Cumulative studies indicate that adiponectin elicits beneficial effects that oppose lipotoxicity, including suppression of TNF and NF-κB activation along with elevation of energy expenditure [ 138 ]. Adiponectin also activates AMPK and PPARα and recently it was shown that AMPK phosphorylates HMGCR and suppresses Chol synthesis [ 139 ]. Chol synthesis inhibition with statins could have beneficial effects on NAFLD [ 140 ].…”

Section: Cholesterol and Hccmentioning

confidence: 99%

From Liver Fat to Cancer: Perils of the Western Diet

Kim

Karin

2021

Cancers

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Hepatocellular carcinoma (HCC), the most common type of primary liver cancer provides the prototypical example of an obesity-related cancer. The obesity epidemic gave rise to an enormous increase in the incidence of non-alcoholic fatty liver disease (NAFLD), a condition that affects one third of American adults. In about 20% of these individuals, simple liver steatosis (hepatosteatosis) progresses to non-alcoholic steatohepatitis (NASH) characterized by chronic liver injury, inflammation, and fibrosis. In addition to liver failure, NASH greatly increases the risk of HCC. Here we discuss the metabolic processes that control the progression from NAFLD to NASH and from NASH to HCC, with a special emphasis on the role of free-non-esterified cholesterol in the process.

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Inhibition of Adenosine Monophosphate–Activated Protein Kinase–3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Signaling Leads to Hypercholesterolemia and Promotes Hepatic Steatosis and Insulin Resistance

Cited by 61 publications

References 48 publications

Effects and Mechanisms of Chitosan and ChitosanOligosaccharide on Hepatic Lipogenesis and Lipid Peroxidation, Adipose Lipolysis, and Intestinal Lipid Absorption in Rats with High-Fat Diet-Induced Obesity

Effects and Mechanisms of Chitosan and ChitosanOligosaccharide on Hepatic Lipogenesis and Lipid Peroxidation, Adipose Lipolysis, and Intestinal Lipid Absorption in Rats with High-Fat Diet-Induced Obesity

Comparative Effects and Mechanisms of Chitosan and Its Derivatives on Hypercholesterolemia in High-Fat Diet-Fed Rats

From Liver Fat to Cancer: Perils of the Western Diet

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